Pyrazolo[1,5-a]pyridines and medicines containing the same

ABSTRACT

Compounds represented by the general formula:  
                 
 
     [wherein R 1  represents methoxy, ethyl, methylthio, etc., R 2 , R 3  and R 4  each represent hydrogen, a halogen, etc., R 5  and R 6  each represent —X 5 —X 6 —X 7  (wherein X 5  represents a single bond or —CO—, X 6  represents a single bond, —NR 3a , etc. and X 7  and R 3a  each represent hydrogen, C 1-10  alkyl, etc.), and Ar represents phenyl, pyridyl, etc.], salts thereof and hydrates of the foregoing.

TECHNICAL FIELD

[0001] The present invention relates to novel compounds havingCorticotropin-Releasing Factor receptor antagonistic activity, saltsthereof and hydrates of the foregoigng, to process for produicing thesame and to the use of the same as medicine.

BACKGROUND ART

[0002] Corticotropin-Releasing Factor (hereinafter abbreviated as “CRF”)is a neuropeptide consisting of 41 amino acids which was first isolatedfrom ovine hypothalamus [Science, 213, 1394 (1981)], after which itspresence was also confirmed in rats [Proc. Natl. Acad. Sci. USA, 80,4851 (1983)] and in humans [EMBO J. 5, 775 (1983)]. CRF is most abundantin the pituitary gland and hypothalamus, and is also widely distributedthroughout the cerebral cortex, cerebellum and other areas of the brain.Its presence has also been confirmed in peripheral tissue such as theplacenta, adrenal gland, lung, liver, pancrea and digestive tract [J.Clin. Endocrinol. Metab., 65, 176 (1987), J. Clin. Endocrinol. Metab.,67, 768 (1988), Regul. Pept., 18, 173 (1987), Peptides, 5 (Suppl. 1), 71(1984)]. Two subtype CRF receptor has been described, CRF1 and CRF2, andthe CRF1 receptor is reported to be widely distributed in the cerebralcortex, cerebellum, olfactory bulb, pituitary gland, amygdaloid nucleusand elsewhere. Recently, 2 subtypes of the CRF2 receptor have beenconfirmed, CRF2α and CRF2β, of which it has been discovered that CRF2αreceptors are abundantly distributed in the hypothalamus, septal nuleusand choroid plexus, while CRF2β receptors are primarily distributed inperipheral tissue such as the skeletal muscle, or in the cerebral bloodvessels of the central nervous system [J. Neuroscience, 15(10)6340(1995); Endocrinology, 137, 72 (1996); BBA, 1352, 129 (1997)]. The factthat each of these receptors has a different distribution profilesuggests that their roles are also different. CRF is produced andsecreted in the hypothalamus and promotes stress-induced release ofadrenocorticotropic hormone (ACTH) [Recent Prog. Horm. Res., 39, 245(1983)]. In addition to its endocrine role, CRF also functions as aneurotransmitter or neuromodulator in the brain, integratingelectrophysiological, autonomic and behavioral changes in response tostress [Brain Res. Rev., 15, 71 (1990); Pharmacol. Rev., 43, 425(1991)].

[0003] CRF has been implicated in a variety of disease to date, asindicated by the following publications.

[0004] It was reported that elevated concentrations of CRF in thecerebrospinal fluid of patients with major depression compared withhealthy controls [Am. J. Psychiatry, 144(7), 873 (1987)]; CRF-mRNAlevels in the hypothalamus of depressive patients are higher than thatof healthy individuals [Am. J. Psychiatry, 152, 1372 (1995)]; CRFreceptors in cerebral cortex are reduced in suicide victims [Arch. Gen.Psychiatry, 45, 577 (1988)]; plasma ACTH increase is diminished withadministration of CRF to depressive patients [N. Engl. J. Med., 314,1329 (1986)]; CRF levels in the cerebrospinal fluid of some anxietypatients with obsessive-compulsive disorder, posttraumatic stressdisorder or Tourette's syndrome are higher than in that of healthyindividuals [Arch. Gen. Psychiatry, 51, 794 (1994); Am. J. Psychiatry,154, 624 (1997); Biol. Psychiatry, 39, 776 (1996)]; plasma ACTH increaseis diminished with administration of CRF to panic disorder patients [Am.J. Psychiatry, 143, 896 (1986)]; anxiety behavior has been observed inexperimental animals by central administration of CRF [Brain Res., 574,70 (1992); J. Neurosci., 10(1), 176 (1992)]. In addition, anxietybehavior is observed more frequently in CRF overexpressing mice than innormal mice [J. Neurosci., 14(5), 2579 (1994)], and CRF levels in thelocus coeruleus are reduced by administration of anxiolytics [J.Pharmaco. Exp. Ther., 258, 349 (1991)]. Also, the peptide CRF antagonistα-helical CRF(9-41) exhibits an anxiolytic effect in animal models[Brain Res., 509, 80 (1990); Regulatory Peptides, 18, 37 (1987); J.Neurosci., 14(5), 2579 (1994)]; abnormal behavior withdrawal fromalcohol or addictive drugs such as cocaine are inhibited by the peptideCRF antagonist α-helical CRF(9-41) [Psychopharmacology, 103, 227(1991)]; CRF inhibits sexual behavior in rats [Nature, 305, 232 (1983)];CRF reduces sleep in rats and is thus implicated the involvement insleep disorder [Pharmacol. Biochem. Behav., 26, 699 (1987)]; the peptideCRF antagonist α-helical CRF(9-41) suppresses brain damage orelectroencephalogram disturbances due to brain ischemia or NMDA receptoractivation [Brain Res., 545, 339 (1991), Brain Res., 656, 405 (1994)];CRF elicits electroencephalogram and induces convulsions [Brain Res.,278, 332 (1983)]; cerebrospinal CRF levels are elevated in schizophrenicpatients compared with healthy individuals [Am. J. Psychiatry, 144(7),873 (1987)]; CRF contents in cerebral cortex is reduced in Alzheimer'spatients, Parkinson's patients and progressive supranuclear palsypatients [Neurology, 37, 905 (1987)]; and CRF is reduced in the gangliain Huntington's disease [Brain Res., 437, 355 (1987), Neurology, 37, 905(1987)]. In addition, CRF administration has been found to enhancelearning and memory in rats [Nature, 378, 284 (1995);Neuroendocrinology, 57, 1071 (1993)], and CRF levels of cerebrospinalfluid are reduced in amyotrophic lateral sclerosis patients.Oversecretion of ACTH and adrenocorticosteroids are exhibited in CRFoverexpressing mice, these mice display abnormalities similar toCushing's syndrome, including muscular atrophy, alopecia and infertility[Endocrinology, 130(6), 3378 (1992)]; cerebrospinal CRF levels areelevated in anorexia nervosa patients compared with healthy individuals,and plasma ACTH increase is low with administration of CRF to anorexianervosa patients [J. Clin. Endocrinol. Metab., 62, 319 (1986)]; and CRFsuppress food consumption in experimental animals [Neuropharmacology,22(3A), 337 (1983)]. Moreover, the peptide CRF antagonist α-helicalCRF(9-41) reverses stress-induced reduction in food intake in animalmodels [Brain Res. Bull., 17(3), 285 (1986)]; CRF has suppressed bodyweight gain in genetically obese animals [Physiol. Behav., 45, 565(1989)]; a link has been suggested between low CRF levels and obesitysyndrome [Endocrinology, 130, 1931 (1992)]; the anorexic action and bodyweight-reducing effects of serotonin reuptake inhibitors has beenpossibly linked to CRF release [Pharmacol. Rev., 43, 425 (1991)]; andCRF acts centrally or peripherally to inhibit gastric contraction andreduce gastric emptying [Regulatory Peptides, 21, 173 (1988); Am. J.Physiol., 253, G241 (1987)]. Furthermore, abdominal surgery-inducedreduced gastric function is reversed by the peptide CRF antagonistα-helical CRF(9-41) [Am. J. Physiol., 262, G616 (1992)]; and CRFpromotes secretion of bicarbonate ion in the stomach, thereby loweringgastric acid secretion and suppressing cold restraint stress ulcers [Am.J. Physiol., 258, G152 (1990)]. Also, administration of CRF increasesulcers in non-restraint stress animals [Life Sci., 45, 907 (1989)], andCRF suppresses small intestinal transit and promotes large intestinaltransit, and defecation is induced. In addition, the peptide CRFantagonist α-helical CRF(9-41) has a inhibiting effect against restraintstress-induced gastric acid secretion reduced gastric emptying, andsmall intestinal transit and accelerated large intestinal transit[Gastroenterology, 95, 1510 (1988)]; psychological stress in healthyindividuals increases anxiety or sensations of gas and abdominal painduring colonic distension and CRF lowers the discomfort threshold[Gastroenterol., 109, 1772 (1995); Neurogastroenterol. Mot., 8, 9(1996)]; irritable bowel syndrome patients experience excessiveacceleration of colonic motility with CRF administration compared tohealthy individuals [Gut, 42, 845 (1998)]; administration of CRFincreases blood pressure, heart rate and body temperature, while thepeptide CRF antagonist α-helical CRF(9-41) suppresses stress-inducedincreases in blood pressure, heart rate and body temperature [J.Physiol., 460, 221 (1993)]; CRF production is increased locally ininflammation sites in experimental animals and in the synovial fluid ofrheumatic arthritis patients [Science, 254, 421 (1991); J. Clin.Invest., 90, 2555 (1992); J. Immunol., 151, 1587 (1993)]; CRF provokesdegranulation of mast cells and promotes vascular permeability[Endocrinology, 139(1), 403 (1998); J. Pharmacol. Exp. Ther., 288(3),1349 (1999)]; CRF is detected in autoimmune thyroiditis patients [Am. J.Pathol., 0.145, 1159 (1994)]; administration of CRF to experimentalautoimmune encephalomyelitis rats has notably suppressed progression ofsymptoms such as paralysis [J. Immumol., 158, 5751 (1997)]; andurocortin (a CRF analogue) has increased growth hormone secretion in apituitary adenoma culture system from an acromegalia patient [Endocri.J. 44, 627 (1997)]. Furthermore, CRF simulates secretion of cytokinessuch as interleukin-1 and interleukin-2 by leukocytes [J. Neuroimmunol.,23, 256 (1989); Neurosci. Lett., 120, 151 (1990)]; and CRFadministration and stress both suppress T lymphocyte proliferation andnatural killer cell activity. The peptide CRF antagonist α-helicalCRF(9-41) improves the reduced function of these immune cells caused byCRF administration or stress [Endocrinology, 128(3), 1329 (1991)], andventilation is notably increased by administration of CRF [Eur. J.Pharmacol., 182, 405 (1990)]. Finally, aggravated breathing and insomniahave been observed as a result of CRF administration to elderly patientsunder chronic artificial respiration [Acta Endocrinol. Copenh., 127, 200(1992)].

[0005] The research cited above suggests that CRF antagonists may beexpected to exhibit excellent effects for treatment or prevention ofdepression and depressive symptoms such as major depression,single-episode depression, recurrent depression, depression-inducedchild abuse and postpartum depression, mania, anxiety, generalizedanxiety disorder, panic disorder, phobias, obsessive-compulsivedisorder, posttraumatic stress disorder, Tourette's syndrome, autism,affective disorder, dysthymia, bipolar disorder, cyclothymicpersonality, schizophrenia, Alzheimer's disease, senile dementia ofAlzheimer's type, neurodegenerative disease such as Parkinson's diseaseand Huntington's disease, multi-infarct dementia, senile dementia,anorexia nervosa, increased appetite and other eating disorders,obesity, diabetes, alcohol dependence, pharmacophilia for drugs such ascocaine, heroin or benzodiazepines, drug or alcohol withdrawal symptoms,sleep disorder, insomnia, migraine, stress-induced headache, musclecontraction induced headache, ischemic neuronal damage, excitotoxicneuronal damage, stroke, progressive supranuclear palsy, amyotrophiclateral sclerosis, multiple sclerosis, muscular spasm, chronic fatiguesyndrome, psychosocial dwarfism, epilepsy, head trauma, spinal cordinjury, cheirospasm, spasmodic torticollis, cervicobrachial syndrome,primary glaucoma, Meniere's syndrome, autonomic imbalance, alopecia,neuroses such as cardiac neurosis, gastric neurosis and bladderneurosis, peptic ulcer, irritable bowel syndrome, ulcerative colitis,Crohn's disease, diarrhea, constipation, postoperative ileus,stress-associated gastrointestinal disorders and nervous vomiting,hypertension, cardiovascular disorders such as angina pectoris nervosa,tachycardia, congestive heart failure, hyperventilation syndrome,bronchial asthma, apneusis, sudden infant death syndrome, inflammatorydisorders (for example, rheumatic arthritis, osteoarthritis, lumbago,etc.), pain, allergosis (for example, atopic dermatitis, eczema, hives,psoriasis, etc.), impotence, menopausal disorder, fertilizationdisorder, infertility, cancer, HIV infection-related immune dysfunction,stress-induced immune dysfunction, hemorrhagic stress, Cushing'ssyndrome, thyroid function disorder, encephalomyelitis, acromegaly,incontinence, osteoporosis, and the like. As examples of CRF antagoniststhere have been reported peptide CRF receptor antagonists withmodifications or deletions of portions of the amino acid sequence ofhuman or other mammalian CRF, and such antagonists have shown ACTHrelease-inhibiting effects or anxiolytic effects [Science, 224,889(1984), J. Pharmacol. Exp. Ther., 269, 564 (1994), Brain ResearchReviews, 15, 71 (1990)]. However, peptide derivatives have low utilityvalue as drugs from the standpoint of pharmacokinetics including theirchemical stability in the body, oral absorption, bioavailability andmigration into the brain.

[0006] On the other hand, the following non-peptide CRF antagonists havealso been reported.

[0007] [1] Compounds represented by the formula:

[0008] [wherein R¹ represents NR⁴R⁵, etc.; R² represents C₁₋₆ alkyl,etc.; R³ represents C₁₋₆ alkyl, etc.; R⁴ represents C₁₋₆ alkyl, etc.; R⁵represents C₁₋₈ alkyl, etc.; and Ar represents phenyl, etc.],stereoisomers thereof or pharmacologically acceptable acid additionsalts of the foregoing(WO97/29109);

[0009] [2] Compounds represented by the formula:

[0010] [wherein the dotted lines represent single bonds or double bonds;A represents CR⁷, etc.; B represents NR¹R², etc.; J and K are the sameor different and represent nitrogen, etc.; D and E are the same ordifferent and represent nitrogen, etc.; G represents nitrogen, etc.; R₁represents C₁-C₆ alkyl, etc.; R² represents C₁-C₁₋₂ alkyl, etc.; and R₇represents hydrogen, etc.] or pharmacologically acceptable salts thereof(WO98/08847);

[0011] [3] The anilinopyrimidine compounds described in WO95/10506, thepyrazolopyridine compounds described in WO95/34563, the pyrazolecompounds described in WO94/13661, the pyrazole compounds andpyrazolopyrimidine compounds described in WO94/13643, the aminopyrazolecompounds described in WO94/18644, the pyrazolopyrimidine compoundsdescribed in WO94/13677, the pyrrolopyrimidine compounds described inWO94/13676, the thiazole compounds described in EP-659747 and EP-611766,the anilinopyrimidine compounds described in J. Med. Chem., 39,4358(1996), the anilinotriazine compounds described in ibid. 39,4354(1996) and the thienopyrimidine compounds described in WO97/29110;and

[0012] [4] As pyrazolo[1,5-a]pyridine compounds, the compoundsdescribed, for example, in EP433854, EP433853 or U.S. Pat. No.5,445,943.

DISCLOSURE OF THE INVENTION

[0013] As mentioned above, it is ardently desired to provide CRFreceptor antagonists which are useful as drugs, but clinically effectiveagents that exhibit excellent CRF receptor antagonism and satisfy therequirements of pharmacological activity, dosage and safety as medicineshave not yet been discovered. It is therefore an object of the presentinvention to investigate and discover such excellent CRF receptorantagonists.

[0014] As a result of much diligent examination and research in light ofthe circumstances described above, the present inventors have discoverednovel pyrazolo[1,5-a]pyridine compounds exhibiting excellent CRFreceptor antagonism.

[0015] The invention provides:

[0016] <1> a compound represented by the general formula:

[0017] [wherein R¹ represents hydrogen, halogen, nitro, cyano or theformula -G¹-R^(1a) (wherein G¹ represents a single bond, methylene,oxygen, sulfur, sulfinyl, sulfonyl, —C(O)—, —C(O)O—, —OC(O)—, —NR^(1b)—,—C(O)—NR^(1b)—, —S(O)₂—NR^(1b)—, —NR^(1b)—C(O)— or —NR^(1b)—S(O)₂—; andR^(1a) and R^(1b) each independently represent hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl or C₅₋₈ cycloalkenyl);

[0018] R², R³ and R⁴ each independently represent hydrogen, halogen,cyano, nitro, hydroxyl, C₆₋₁₄ aryl, a 5- to 14-membered heteroaryl groupor the formula -G²-R^(2a) (wherein G² represents a single bond, C₁₋₆alkylene, oxygen, sulfur, sulfinyl, sulfonyl, —C(O)—, —C(O)O—, —OC(O)—,—NR^(2b), C(O)—NR^(2b)—, —S(O)₂—NR^(2b)—, —NR^(2b)—C(O)— or—NR^(2b)—S(O)₂—;

[0019] R^(2a) and R^(2b) each independently represent hydrogen, C₁₋₆alkyl optionally substituted with 1-3 halogen, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₈ cycloalkyl or C₅₋₈ cycloalkenyl);

[0020] R₂ and R₃ or R₃ and R⁴ may bond together to form a 5- to7-membered ring optionally containing 1 to 4 hetero atoms in the ringand optionally containing carbonyl in the ring;

[0021] R⁵ and R⁶ each independently represent the formula —X⁵—X⁶—X⁷(wherein X⁵ represents a single bond or —CO—; X⁶ represents a singlebond, —NR^(3a)—, oxygen, sulfur, sulfinyl, sulfonyl, C₁₋₁₀ alkylene,C₂₋₁₀ alkenylene or C₂₋₁₀ alkynylene; and X⁷ and R^(3a) eachindependently represent hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl, C₆₋₁₄ aryl, a 5- to14-membered heteroaryl group, a 4- to 14-membered heterocyclic group, a9- to 11-membered benzene fused ring group, an 8- to 11-memberedheteroaryl fused ring group or a bicyclic 7- to 12-membered hydrocarbonring group);

[0022] R⁵ and R⁶ may bond together to form a 5- to 10-membered ringoptionally containing 1 to 4 hetero atoms in the ring and optionallycontaining carbonyl in the ring;

[0023] R⁶ and R² may bond together to form a 6- to 7-membered ringoptionally containing 1 or 2 hetero atoms in the ring and optionallycontaining carbonyl in the ring; and

[0024] Ar represents C₆₋₁₄ aryl, a 5- to 14-membered heteroaryl group, a9- to 11-membered benzene fused ring group or an 8- to 11-memberedheteroaryl fused ring group; with the proviso that R^(1a), R^(1b),R^(3a), X⁶, X⁷ and Ar may each independently have 1 to 4 groups selectedfrom Substituent Group A below;

[0025] <Substituent Group A>

[0026] The group consisting of methylenedioxy, ethylenedioxy and theformula -V¹-V²-V³ (wherein V¹ represents a single bond, C₁₋₆ alkylene,C₂₋₆ alkenylene, C₂₋₆ alkynylene, oxygen, sulfur, carbonyl, —CO—O—,—O—CO— or —NR^(3b)—; V² represents a single bond or C₁₋₆ alkylene; andV³ and R^(3b) each independently represent C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl, C₆₋₁₄ aryl, a 5- to14-membered heteroaryl group, a 4- to 14-membered heterocyclic group,hydrogen, halogen, hydroxyl, cyano, C₁₋₆ alkoxy or the formula—N(R^(3c))R^(3d) (wherein R^(3c) and R^(3d) each independently representhydrogen or C₁₋₆ alkyl))],

[0027] a salt thereof or a hydrate of the foregoing.

[0028] <2> a compound according to <1>, a salt of the compound or ahydrate of the foregoing, wherein R¹ is the formula -G¹⁰-R¹⁰ (whereinG¹⁰ represents a single bond, methylene, oxygen, sulfur, sulfinyl orsulfonyl and R¹⁰ represents C₁₋₆ alkyl optionally substituted with 1 to3 halogen, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₃₋₈ cycloalkyl);

[0029] <3> a compound according to <2>, a salt of the compound or ahydrate of the foregoing, wherein R¹⁰ is methyl, ethyl, n-propyl,iso-propyl, trifluoromethyl, difluoromethyl, monofluoromethyl,cyclopropyl or cyclobutyl;

[0030] <4> a compound according to <1>, a salt of the compound or ahydrate of the foregoing, wherein R¹ is methoxy;

[0031] <5> a compound according to <1>, a salt of the compound or ahydrate of the foregoing, wherein R¹ is ethyl;

[0032] <6> a compound according to <1>, a salt of the compound or ahydrate of the foregoing, wherein R¹ is methylthio;

[0033] <7> a compound according to any one of <1> to <6>, a salt of thecompound or a hydrate of the foregoing,

[0034] wherein R², R³ and R⁴ each independently represent hydrogen,halogen, cyano, nitro, hydroxyl, or the formula -G²⁰-R²⁰ (wherein G²⁰represents a single bond, oxygen, sulfur, sulfinyl or sulfonyl, and R²⁰represents C₁₋₆ alkyl optionally substituted with 1 to 3 halogen, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl or C₃₋₈ cycloalkyl);

[0035] <8> a compound according to any one of <1> to <6>, a salt of thecompound or a hydrate of the foregoing, wherein R², R³ and R⁴ arehydrogen;

[0036] <9> a compound according to any one of <1> to <8>, a salt of thecompound or a hydrate of the foregoing, wherein Ar is phenyl,1,3-benzodioxolyl, naphthyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl,thienyl, furanyl, imidazolyl, thiazolyl, quinolinyl, isoquinolinyl,indolinyl, benzofuranyl, benzothienyl, oxazolyl or isoxazolyl, and Armay have 1 to 4 groups selected from Substituent Group B below;

[0037] <Substituent Group B>

[0038] The group consisting of halogen, cyano, hydroxyl, nitro,methylenedioxy, ethylenedioxy, the formula -V⁴-V⁵ (wherein V⁴ representsa single bond, oxygen, sulfur, sulfinyl or sulfonyl and V⁵ representsC₁₋₆ alkyl optionally substituted with 1 to 3 halogen or C₃₋₈cycloalkyl) and the formula —N(R^(5a))R^(5b) (wherein R^(5a) and R^(5b)each independently represent hydrogen or C₁₋₆ alkyl);

[0039] <10> A compound according to any one of <1> to <9>, a salt of thecompound or a hydrate of the foregoing, wherein Ar is phenyl or pyridyl,and Ar may optionally have 1 to 3 groups selected from Substituent GroupB in <9>;

[0040] <11> a compound according to <9> or <10>, a salt of the compoundor a hydrate of the foregoing, wherein Substituent Group B is the groupconsisting of halogen, cyano, C₁₋₆ alkyl optionally substituted with 1to 3 halogen, C₃₋₈ cycloalkyl, dimethylamino and C₁₋₆ alkoxy optionallysubstituted with 1 to 3 halogen;

[0041] <12> a compound according to any one of <1> to <8>, a salt of thecompound or a hydrate of the foregoing, wherein Ar is the formula:

[0042] (wherein R⁴⁰ and R⁴¹ each independently represent methoxy,ethoxy, ethyl, methyl, dimethylamino or halogen, R⁴² representshydrogen, methoxy, methyl, dimethylamino or halogen, and Z¹ and Z² eachindependently represent methine or nitrogen);

[0043] <13> a compound according to <12>, a salt of the compound or ahydrate of the foregoing, wherein Z¹ and Z² are methine;

[0044] <14> a compound according to any one of <1> to <13>, a salt ofthe compound or a hydrate of the foregoing, wherein X⁵ is a single bond,and X⁶ is a single bond, C₁₋₆ alkylene optionally having 1 to 3 groupsselected from Substituent Group A, C₂₋₆ alkenylene optionally having 1to 3 groups selected from Substituent Group A or C₂₋₆ alkynyleneoptionally having 1 to 3 groups selected from Substituent Group A.

[0045] <15> a compound according to any one of <1> to <13>, a salt ofthe compound or a hydrate of the foregoing, wherein X⁵ is a single bond,and X⁶ is a single bond or C₁₋₆ alkylene optionally having 1 to 3 groupsselected from Substituent Group C below;

[0046] <Substituent Group C>

[0047] The group consisting of halogen, hydroxyl, C₁₋₆ alkoxy, nitrile,C₃₋₈ cycloalkyl, and C₁₋₆ alkyl;

[0048] <16> a compound according to any one of <1> to <13>, a salt ofthe compound or a hydrate of the foregoing, wherein X⁵ is a single bond,and X⁶ is a single bond, 1,2-ethylene or methylene;

[0049] <17> a compound according to any one of <1> to <16>, a salt ofthe compound or a hydrate of the foregoing, wherein X⁷ is C₁₋₁₀ alkyloptionally having 1 to 3 groups selected from Substituent Group A, C₂₋₁₀alkenyl optionally having 1 to 3 groups selected from Substituent GroupA, C₂₋₁₀ alkynyl optionally having 1 to 3 groups selected fromSubstituent Group A, C₃₋₈ cycloalkyl optionally having 1 to 3 groupsselected from Substituent Group A, C₅₋₈ cycloalkenyl optionally having 1to 3 groups selected from Substituent Group A, C₆₋₁₄ aryl optionallyhaving 1 to 3 groups selected from Substituent Group A, a 5- to14-membered heteroaryl group optionally having 1 to 3 groups selectedfrom Substituent Group A, a 4- to 14-membered heterocyclic groupoptionally having 1 to 3 groups selected from Substituent Group A or abicyclic 7- to 12-membered hydrocarbon ring group optionally having 1 to3 groups selected from Substituent Group A;

[0050] <18> a compound according to any one of <1> to <16>, a salt ofthe compound or a hydrate of the foregoing, wherein X⁷ is C₁₋₁₀ alkyloptionally having 1 to 3 groups selected from Substituent Group A, C₃₋₈cycloalkyl optionally having 1 to 3 groups selected from SubstituentGroup A, a 5- to 6-membered heteroaryl group optionally having 1 to 3groups selected from Substituent Group A or a 4- to 7-memberedheterocyclic group optionally having 1 to 3 groups selected fromSubstituent Group A;

[0051] <19> a compound according to any one of <1> to <16>, a salt ofthe compound or a hydrate of the foregoing, wherein X⁷ is C₁₋₁₀ alkyloptionally having 1 to 3 groups selected from Substituent Group D below,C₃₋₈ cycloalkyl optionally having 1 to 3 groups selected fromSubstituent Group D below, a 5- to 6-membered heteroaryl groupoptionally having 1 to 3 groups selected from Substituent Group D belowor a 4- to 7-membered heterocyclic group optionally having 1 to 3 groupsselected from Substituent Group D below;

[0052] <Substituent Group D>

[0053] The group consisting of halogen, hydroxyl, C₁₋₆ alkoxy, nitrile,C₃₋₈ cycloalkyl, dimethylamino and C₁₋₆ alkyl; <20> a compound accordingto any one of <1> to <16>, a salt of the compound or a hydrate of theforegoing, wherein X⁷ is hydrogen, C₁₋₁₀ alkyl optionally having 1 or 2groups selected from Substituent Group E below, C₃₋₈ cycloalkyloptionally having 1 or 2 groups selected from Substituent Group E below,tetrahydrofuranyl optionally having 1 or 2 groups selected fromSubstituent Group E below, tetrahydrothiophenyl optionally having 1 or 2groups selected from Substituent Group E below, dihydropyranyloptionally having 1 or 2 groups selected from Substituent Group E below,tetrahydropyranyl optionally having 1 or 2 groups selected fromSubstituent Group E below, dioxolanyl optionally having 1 or 2 groupsselected from Substituent Group E below, pyrrolidin-2-onyl optionallyhaving 1 or 2 groups selected from Substituent Group E below,dihydrofuran-2-onyl optionally having 1 or 2 groups selected fromSubstituent Group E below, furanyl optionally having 1 or 2 groupsselected from Substituent Group E below, thienyl optionally having 1 or2 groups selected from Substituent Group E below, pyrrolidinyloptionally having 1 or 2 groups selected from Substituent Group E below,piperidyl optionally having 1 or 2 groups selected from SubstituentGroup E below, oxazolyl optionally having 1 or 2 groups selected fromSubstituent Group E below, isoxazolyl optionally having 1 or 2 groupsselected from Substituent Group E below, thiazolyl optionally having 1or 2 groups selected from Substituent Group E below, pyrrolyl optionallyhaving 1 or 2 groups selected from Substituent Group E below, pyrazolyloptionally having 1 or 2 groups selected from Substituent Group E below,morpholinyl optionally having 1 or 2 groups selected from SubstituentGroup E below, dioxanyl optionally having 1 or 2 groups selected fromSubstituent Group E below or pyridyl optionally having 1 or 2 groupsselected from Substituent Group E below;

[0054] <Substituent Group E>

[0055] The group consisting of hydroxyl, methyl, ethyl, methoxy,dimethylamino, cyano, chlorine and fluorine;

[0056] <21> a compound according to <20>, a salt of the compound or ahydrate of the foregoing, wherein Substituent Group E is the groupconsisting of methyl, methoxy, dimethylamino, chlorine and fluorine;

[0057] <22> a compound according to any one of <1> to <16>, a salt ofthe compound or a hydrate of the foregoing, wherein X⁷ is hydrogen,C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, tetrahydrofuranyl, tetrahydrothiophenyl,dihydropyranyl, tetrahydropyranyl, dioxolanyl, pyrrolidin-2-onyl,dihydrofuran-2-onyl, furanyl, thienyl, pyrrolidinyl, piperidyl,oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, pyrazolyl, morpholinyl,dioxanyl or pyridyl;

[0058] <23> a compound according to any one of <1> to <16>, a salt ofthe compound or a hydrate of the foregoing, wherein X⁷ is hydrogen,C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydropyranyl, dioxolanyl, furanyl, thienyl, oxazolyl, dioxanyl,pyridyl, piperidyl or thiazolyl;

[0059] <24> a compound represented by the general formula:

[0060] [wherein R^(7a) represents hydrogen, nitro, —NO or —NHR^(7d)(wherein R^(7d) represents hydrogen, t-butoxycarbonyl orbenzyloxycarbonyl);

[0061] R^(7c) represents methylene, oxygen or sulfur; and

[0062] R^(7b) represents hydrogen, halogen, the formula:

[0063] (wherein R^(8a) and R^(8b) each independently represent hydrogenor C₁₋₆ alkyl, or R^(8a) and R^(8b) may bond together to form1,2-ethylene, 1,3-propylene or 2,3-dimethylbutan-2,3-diyl), the formula:

[0064] (wherein R^(8c), R^(8d) and R^(8e) each independently representC₁₋₆ alkyl) or the formula:

[0065] (wherein R⁴⁰ and R⁴¹ each independently represent methoxy,ethoxy, ethyl, dimethylamino, methyl or halogen, R⁴² representshydrogen, methoxy, methyl or halogen, and Z¹ and Z² each independentlyrepresent methine or nitrogen), with the proviso that compoundssatisfying the following conditions (1), (2) or (3) are not included inthe above definitions:

[0066] (1) R^(7c) is oxygen, R^(7b) is hydrogen and R^(7a) is hydrogen,nitro, —NO or —NH₂, (2) R^(7c) is sulfur, R^(7b) is hydrogen and R^(7a)is nitro or —NH₂, or (3) R^(7c) is methylene, R^(7b) is hydrogen andR^(7a) is —NO],

[0067] a salt thereof or a hydrate of the foregoing;

[0068] <25> a compound according to <24>, a salt of the compound or ahydrate of the foregoing, wherein R_(7a) and R^(7b) are hydrogen;

[0069] <26> a compound according to <24>, a salt of the compound or ahydrate of the foregoing, wherein R^(7b) is not hydrogen;

[0070] <27> a compound represented by the general formula:

[0071] [wherein R⁵ and R⁶ have the same definitions as R⁵ and R⁶ in <1>,respectively;

[0072] R^(7c) represents methylene, oxygen or sulfur; and

[0073] R^(7e) represents halogen, the formula:

[0074] (wherein R^(8a) and R^(8b) each independently represent hydrogenor C₁₋₆ alkyl, or R^(8a) and R_(8b) may bond together to form1,2-ethylene, 1,3-propylene or 2,3-dimethylbutan-2,3-diyl), or theformula:

[0075] (wherein R^(8c), R^(8d) and R^(8e) each independently representC₁₋₆ alkyl)],

[0076] a salt thereof or a hydrate of the foregoing;

[0077] <28> a Corticotropin-Releasing Factor (CRF) receptor antagonistcomprising a compound according to <1>;

[0078] <29> a Corticotropin-Releasing Factor (CRF)-1 receptor orCorticotropin-Releasing Factor (CRF)-2 receptor antagonist comprising acompound according to <1>;

[0079] <30> a therapeutic or prophylactic agent for a disease associatedwith Corticotropin-Releasing Factor (CRF), comprising a compoundaccording to <1>;

[0080] <31> a therapeutic or prophylactic agent for depression,depressive symptom, mania, anxiety, generalized anxiety disorder, panicdisorder, phobias, obsessive-compulsive disorder, posttraumatic stressdisorder, Tourette's syndrome, autism, affective disorder, dysthymia,bipolar disorder, cyclothymic personality or schizophrenia, comprising acompound according to <1>;

[0081] <32> a therapeutic or prophylactic agent for a depressive symptomwhich is major depression, single-episode depression, recurrentdepression, depression-induced child abuse or postpartum depression,comprising a compound according to <1>;

[0082] <33> a therapeutic or prophylactic agent for peptic ulcer,irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea,constipation, postoperative ileus, stress-associated gastrointestinaldisorders or nervous vomiting, comprising a compound according to <1>;

[0083] <34>a therapeutic or prophylactic agent for Alzheimer's disease,senile dementia of Alzheimer's type, neurodegenerative disease,multi-infarct dementia, senile dementia, anorexia nervosa, eatingdisorder, obesity, diabetes, alcohol dependence, pharmacophilia, drugwithdrawal symptoms, alcohol withdrawal symptoms, sleep disorder,insomnia, migraine, stress-induced headache, muscle contraction inducedheadache, ischemic neuronal damage, excitotoxic neuronal damage, stroke,progressive supranuclear palsy, amyotrophic lateral sclerosis, multiplesclerosis, muscular spasm, chronic fatigue syndrome, psychosocialdwarfism, epilepsy, head trauma, spinal cord injury, cheirospasm,spasmodic torticollis, cervicobrachial syndrome, primary glaucoma,Meniere's syndrome, autonomic imbalance, alopecia, neurosis,hypertension, cardiovascular disorder, tachycardia, congestive heartfailure, hyperventilation syndrome, bronchial asthma, apneusis, suddeninfant death syndrome, inflammatory disorder, pain, allergosis,impotence, menopausal disorder, fertilization disorder, infertility,cancer, HIV infection-induced immune dysfunction, stress-induced immunedysfunction, hemorrhagic stress, Cushing's syndrome, thyroid functiondisorder, encephalomyelitis, acromegaly, incontinence or osteoporosis,comprising a compound according to <1>;

[0084] <35> the use of a compound according to <1> or a salt thereof forthe manufacture of a Corticotropin-Releasing Factor (CRF) receptorantagonist;

[0085] <36> the use of a compound according to <1> or a salt thereof forthe manufacture of a Corticotropin-Releasing Factor (CRF)-1 receptorantagonist or Corticotropin-Releasing Factor (CRF)-1 receptorantagonist;

[0086] <37> the use of a compound according to <1> or a salt thereof forthe manufacture of a therapeutic or prophylactic agent for depression,depressive symptom, mania, anxiety, generalized anxiety disorder, panicdisorder, phobia, obsessive-compulsive disorder, posttraumatic stressdisorder, Tourette's syndrome, autism, affective disorder, dysthymia,bipolar disorder, cyclothymic personality, schizophrenia, peptic ulcer,irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea,constipation, postoperative ileus, stress-associated gastrointestinaldisorders or nervous vomiting;

[0087] <38> a therapeutic or prophylactic method for a diseaseassociated with Corticotropin-Releasing Factor (CRF) receptor,comprising single or multiple administration of a therapeuticallyeffective dose of a compound according to <1> or a salt thereof to apatient with a disease associated with Corticotropin-Releasing Factor(CRF) receptor.

BEST MODE FOR CARRYING OUT THE INVENTION

[0088] The present invention will now be explained in greater detail.

[0089] Several of the structural formulas given for compounds throughoutthe present specification will represent a specific isomer forconvenience, but the invention is not limited to such specific isomersand encompasses all isomers and isomer mixtures, including geometricisomers, asymmetric carbon-derived optical isomers, stereoisomers andtautomers, implied by the structures of the compounds, of which anyisomer or mixture thereof may be used. The compounds of the inventiontherefore may include those having asymmetric carbons in their moleculesand existing as optically active forms or racemic forms, and all suchcompounds are encompassed by the invention without restrictions. Thereare also no restrictions on any crystalline polymorphism of thecompounds, and any crystal forms may be used alone or in mixtures, whilethe compounds of the invention also include anhydrides and hydrates.Metabolites of the compounds of the present invention, produced bydegradation in the body, are also encompassed by the claims of theinvention.

[0090] The symbols and terms used throughout the present specificationwill now be defined, with a more detailed description of the invention.

[0091] The term “CRF receptor antagonist” as used throughout the presentspecification refers to a substance capable of inactivating CRFreceptors. Such substances also include those capable of attenuating orinhibiting the physiological activity of CRF.

[0092] As diseases included among “diseases associated with CRF” or“diseases associated with CRF receptors” according to the presentspecification there may be mentioned depression and depressive symptoms(major depression, single-episode depression, recurrent depression,depression-induced child abuse, postpartum depression, etc.), mania,anxiety, generalized anxiety disorder, panic disorder, phobias,obsessive-compulsive disorder, posttraumatic stress disorder, Tourette'ssyndrome, autism, affective disorder, dysthymia, bipolar disorder,cyclothymic personality, schizophrenia, peptic ulcer, irritable bowelsyndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation,postoperative ileus, stress-associated gastrointestinal disorders,nervous vomiting, Alzheimer's disease, senile dementia of Alzheimer'stype, neurodegenerative disease, multi-infarct dementia, seniledementia, anorexia nervosa, eating disorder, obesity, diabetes, alcoholdependence, pharmacophilia, drug withdrawal symptoms, alcohol withdrawalsymptoms, sleep disorder, insomnia, migraine, stress-induced headache,muscle contraction induced headache, ischemic neuronal damage,excitotoxic neuronal damage, stroke, progressive supranuclear palsy,amyotrophic lateral sclerosis, multiple sclerosis, muscular spasm,chronic fatigue syndrome, psychosocial dwarfism, epilepsy, head trauma,spinal cord injury, cheirospasm, spasmodic torticollis, cervicobrachialsyndrome, primary glaucoma, Meniere's syndrome, autonomic imbalance,alopecia, neurosis, hypertension, cardiovascular disorder, tachycardia,congestive heart failure, hyperventilation syndrome, bronchial asthma,apneusis, sudden infant death syndrome, inflammatory disorder, pain,allergosis, impotence, menopausal disorder, fertilization disorder,infertility, cancer, HIV infection-related immune dysfunction,stress-induced immune dysfunction, hemorrhagic stress, Cushing'ssyndrome, thyroid function disorder, encephalomyelitis, acromegaly,incontinence, osteoporosis, and the like. The compounds of the inventionare effective for treatment or prevention of the aforementioneddiseases.

[0093] The term “neurodegenerative disease” as used throughout thepresent specification refers to either acute degenerative disease orchronic degenerative disease, and specifically it includes, for example,neuropathies such as subarachnoid hemorrhage, acute stagecerebrovascular disorder, etc. and Alzheimer's disease, Parkinson'sdisease, Huntington's chorea, amyotrophic lateral sclerosis,spinocerebellar degeneration, etc. The term “eating disorder” as usedthroughout the present specification refers to increased appetite,cibophobia and the like. The term “cardiovascular disorder” as usedthroughout the present specification refers to angina pectoris nervosaand the like. The term “inflammatory disorder” as used throughout thepresent specification refers to, for example, rheumatic arthritis,osteoarthritis, lumbago and the like, and the term “allergosis” refersto, for example, atopic dermatitis, eczema, hives, psoriasis and thelike.

[0094] Throughout the present specification, “n-” signifies “normal”,“sec-” signifies “secondary” and “tert-” and “t-” both signify“tertiary”.

[0095] Halogen as used throughout the present specification refers tofluorine, chlorine, bromine, iodine and the like, with fluorine,chlorine or bromine being preferred.

[0096] The terms “C₁₋₆ alkyl” and “C₁₋₁₀ alkyl” used throughout thepresent specification refer respectively to a linear or branched alkylgroup of 1 to 6 carbons and a linear or branched alkyl group of 1 to 10carbons, and are preferably methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-ethylpropyl,n-hexyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl,1,1,2-trimethylpropyl, 1-propylpropyl, 1-methylbutyl, 2-methylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl,3-methylpentyl, or the like, more preferably methyl, ethyl, n-propyl,iso-propyl or tert-butyl, and even more preferably methyl, ethyl oriso-propyl.

[0097] The terms “C₂₋₆ alkenyl” and “C₂₋₁₀ alkenyl” used throughout thepresent specification refer respectively to a linear or branched alkenylgroup of 2 to 6 carbons and a linear or branched alkenyl group of 2 to10 carbons, and preferred examples of such groups include vinyl, allyl,1-propenyl, 2-propenyl, isopropenyl, 2-methyl-1-propenyl,3-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1,3-hexanedienyland 1,6-hexanedienyl.

[0098] The terms “C₂₋₆ alkynyl” and “C₂₋₁₀ alkynyl” used throughout thepresent specification refer respectively to an alkynyl group of 2 to 6carbons and an alkynyl group of 2 to 10 carbons, and preferred examplesof such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 3-methyl-1-propynyl, 1-ethynyl-2propynyl,2-methyl-3-propynyl, 1-pentynyl, 1-hexynyl, 1,3-hexanediynyl and1,6-hexanediynyl.

[0099] The term “C₁₋₆ alkylene” used throughout the presentspecification refers to a divalent group derived by removing anotherhydrogen from any desired position of the aforementioned “C₁₋₆ alkyl”,and as specific examples there may be mentioned methylene, ethylene,methylethylene, propylene, ethylethylene, 1,1-dimethylethylene,1,2-dimethylethylene, trimethylene, 1-methyltrimethylene,1-ethyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene,tetramethylene, pentamethylene and hexamethylene, preferably methyleneand 1,2-ethylene, and more preferably methylene.

[0100] The term “C₂₋₆ alkenylene” used through the present specificationrefers to a divalent group derived by removing another hydrogen from theaforementioned “C₂₋₆ alkenyl”, and as specific examples there may bementioned vinylene, propenylene, butenylene, pentenylene and hexenylene,preferably vinylene, propenylene, butenylene, pentenylene, even morepreferably vinylene, propenylene and butenylene, and even morepreferably 1,2-vinylene and 1,3-propenylene.

[0101] The term “C₂₋₆ alkynylene” used throughout the presentspecification refers to a monovalent group derived by removing anotherhydrogen from the aforementioned “C₂₋₆ alkynylene”, and as specificexamples there may be mentioned ethynylene, propynylene, butynylene,pentynylene and hexynylene, preferably ethynylene, propynylene,butynylene and pentynylene, more preferably ethynylene, propynylene andbutynylene, even more preferably ethynylene and propynylene, and mostpreferably ethynylene.

[0102] The term “C₃₋₈ cycloalkyl” used throughout the presentspecification refers to a cyclic aliphatic hydrocarbon group of 3 to 8carbons, and as examples there may be mentioned cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferablycyclopropyl, cyclobutyl and cyclopentyl, and more preferablycyclopropyl.

[0103] The term “C₅₋₈ cycloalkenyl” used throughout the presentspecification refers to a cycloalkenyl group composed of 5 to 8 carbons,and as examples there may be mentioned cyclopenten-3-yl, cyclohexen-1-yland cyclohexen-3-yl.

[0104] The terms “C₁₋₆ alkoxy” and “C₁₋₁₀ alkoxy” used throughout thepresent specification refer respectively to an oxy group bonded with theaforementioned “C₁₋₆ alkyl” and an oxy group bonded with theaforementioned “C₁₋₁₀ alkyl”, and as examples there may be mentionedmethoxy, ethoxy, n-propoxy, iso-propoxy, sec-propoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, iso-pentyloxy,sec-pentyloxy, n-hexoxy, iso-hexoxy, 1,1-dimethylpropyloxy,1,2-dimethylpropoxy, 2,2-dimethylpropyloxy, 2-ethylpropoxy,1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy,1,1,2-trimethylpropoxy, 1,1,2-trimethylpropoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutyloxy,1,3-dimethylbutyloxy, 2-ethylbutoxy, 1,3-dimethylbutoxy,2-methylpentoxy, 3-methylpentoxy and hexyloxy, preferably methoxy,ethoxy, n-propoxy, iso-propoxy, sec-propoxy, n-butoxy, iso-butoxy,sec-butoxy and tert-butoxy, and more preferably methoxy.

[0105] The terms “C₁₋₆ alkylthio” and “C₁₋₁₀ alkylthio” used throughoutthe present specification refer respectively to a thio group bonded withthe aforementioned “C₁₋₆ alkyl” and a thio group bonded with theaforementioned “C₁₋₁₀ alkyl”, and as examples there may be mentionedmethylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio,iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio,1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio,1-ethylpropylthio, 2-ethylpropylthio, n-hexyl,1-methyl-2-ethylpropylthio, 1-ethyl-2-methylpropylthio,1,1,2-trimethylpropylthio, 1-propylpropylthio, 1-methylbutylthio,2-methylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio,2,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio,2-ethylbutylthio, 2-methylpentylthio and 3-methylpentylthio.

[0106] The term “C₁₋₆ alkylsulfinyl” used throughout the presentspecification refers to a sulfinyl group bonded with the aforementioned“C₁₋₆ alkyl”, and as examples there may be mentioned methylsulfinyl,ethylsulfinyl, n-propylsulfinyl and iso-propylsulfinyl.

[0107] The term “C₁₋₆ alkylsulfonyl” used throughout the presentspecification refers to a sulfonyl group bonded with the aforementioned“C₁₋₆ alkyl”, and as examples there may be mentioned methylsulfonyl,ethylsulfonyl, n-propylsulfonyl and iso-propylsulfonyl.

[0108] The term “C₆₋₁₄ aryl” used throughout the present specificationrefers to an aromatic hydrocarbon ring group of 6 to 14 carbons, whichmay be a monocyclic, bicyclic or tricyclic fused ring. As preferredexamples of such groups there may be mentioned phenyl, indenyl,1-naphthyl, 2-naphthyl, azulenyl, heptalenyl, biphenyl, indacenyl,acenaphthyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl,cyclopentacyclooctenyl and benzocyclooctenyl, preferably phenyl,1-naphthyl or 2-naphthyl, and more preferably phenyl.

[0109] The term “5- to 14-membered heteroaryl group” used throughout thepresent specification refers to a 5- to 14-membered aromatic heterocyclegroup, which is monocyclic, bicyclic or tricyclic group containing atleast one hetero atom selected from N, O and S,. As specific examples ofsuch groups there may be mentioned nitrogen-containing heteroaryl groupssuch as pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazolyl, tetrazolyl, benzotriazolyl, pyrazolyl, imidazolyl,benzimidazolyl, indolyl, isoindolyl, indolidinyl, purinyl, indazolyl,quinolyl, isoquinolyl, quinolidyl, phthalazyl, naphthylidinyl,quinoxalyl, quinazolinyl, cinnolinyl, pteridinyl, imidazotriazinyl,pyrazinopyridazinyl, acridinyl, phenanthridinyl, carbazolyl,carbazolinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, andpyrazolopyridinyl; sulfur-containing heteroaryl groups such as thienyland benzothienyl; oxygen-containing heteroaryl groups such as furyl,pyranyl, cyclopentapyranyl, benzofuryl and isobenzofuryl; and heteroarylgroups containing two or more different hetero atoms, such as thiazolyl,isothiazolyl, benzothiazolyl, benzothiadiazolyl, phenothiazinyl,isoxazolyl, furazanyl, phenoxazinyl, oxazolyl, isoxazoyl, benzoxazolyl,oxadiazolyl, pyrazoloxazolyl, imidazothiazolyl, thienofuranyl,furopyrrolyl, pyridoxazinyl and benzo[1,2,5]thiadiazolyl.

[0110] The “5- to 14-membered heteroaryl group” is preferably pyrrolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl,pyrazolyl, imidazolyl, indolyl, thienyl, benzothienyl, furyl,benzofuranyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl oroxadiazolyl, and more preferably pyridyl, thienyl, furyl, thiazolyl oroxazolyl.

[0111] The term “5- to 6-membered heteroaryl group” used throughout thepresent specification refers to a 5- to 6-membered heteroaryl groupamong the aforementioned 5-to 14-membered heteroaryl group, and asspecific examples there may be mentioned pyrrolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl,thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl andoxadiazolyl, and more preferably pyridyl, thienyl, furyl, thiazolyl oroxazolyl.

[0112] The term “9- to 11-membered benzene fused ring group” usedthroughout the present specification refers to a bicyclic groupcomprising a non-aromatic ring fused with a benzene ring, and having 9to 11 atoms composing the ring of the ring group. The “9- to 11-memberedbenzene fused ring” of a “9- to 11-membered benzene fused ring group” isa ring represented by the following formula:

[0113] (wherein Y¹, Y², Y³, Y⁴ and Y⁵ represent carbonyl, oxygen,sulfur, methylene or the formula —NR³¹— (wherein R³¹ represents hydrogenor C₁₋₆ alkyl), and such a “9- to 11-membered benzene fused ring” ispreferably a ring represented by the formula:

[0114] (wherein Y¹, Y², Y³ and Y⁴ have the same definitions as above),more preferably a ring represented by the formulas:

[0115] and even more preferably a ring represented by the

[0116] formula:

[0117] The term “9- to 11-membered benzene fused ring group” refers to amonovalent group derived by removing a hydrogen atom from any desiredposition of the “9- to 11-membered benzene fused ring”.

[0118] The term “8- to 11-membered heteroaryl fused ring group” usedthroughout the present specification refers to a bicyclic groupcomprising a non-aromatic ring fused with “5- to 6-membered aromaticheterocycle” such as pyridine, thiophene or furan, and having 8 to 11atoms composing the ring of the ring group.

[0119] The term “monocyclic 4- to 8-membered non-aromatic heterocyclicgroup” used throughout the present specification refers to:

[0120] [1] a monocyclic non-aromatic cyclic group,

[0121] [2] having 4 to 8 atoms in the ring of the cyclic group,

[0122] [3] containing 1 or 2 hetero atoms among the atoms of the ring ofthe cyclic group,

[0123] [4] optionally including 1 or 2 double bonds in the ring, and

[0124] [5] optionally including 1 to 3 carbonyl in the ring.

[0125] As specific examples of the “monocyclic 4- to 8-memberednon-aromatic heterocycle” of a “monocyclic 4-to 8-membered non-aromaticheterocyclic group” there may be mentioned pyrrolidine, piperidine,azepane, pyridone, pyrazinone, tetrahydrofuran, tetrahydrothiophene,tetrahydropyran, morpholine, thiomorpholine, piperazine, thiazolidine,dioxane, imidazoline, thiazoline, azetidine, oxetane, thietane,dioxolane, piperidin-4-one, piperidin-3-one, piperidin-2-one,pyrrolidin-2-one, tetrahydrofuran-2-one and 3,4-dihydro-2H-pyran.

[0126] A “monocyclic 4- to 8-membered non-aromatic heterocyclic group”is a monovalent group derived by removing a hydrogen atom from anydesired position of a “monocyclic 4- to 8-membered non-aromaticheterocycle”.

[0127] The term “bicyclic 7- to 12-membered hydrocarbon ring” usedthroughout the present specification refers to a bicyclic hydrocarbonring having 7 to 12 carbon atoms in the ring.

[0128] Specifically, it refers to

[0129] [1] a hydrocarbon ring represented by the formula:

[0130] (wherein M^(1a), M^(2a) and M^(3a) each independently representthe formula —(CH₂)_(m1)— (wherein m1 is an integer of 0-2), with theproviso that M^(1a), M^(2a) and M^(3a) are not all —(CH₂)_(o)—),

[0131] [2] a hydrocarbon ring represented by the formula:

[0132] (wherein M^(6a) represents the formula —(CH₂)_(m3) (wherein m3 isan integer of 0-3)), or

[0133] [3] a hydrocarbon ring represented by the formula:

[0134] (wherein M^(4a) and M^(5a) each independently represent theformula —(CH₂)_(m2)— (wherein m2 is an integer of 0-3)). As specificexamples of the “bicyclic 7- to 12-membered hydrocarbon ring” there maybe mentioned bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane,spiro[2.4]heptane, spiro[2.5]octane,bicyclo[4.4.0]decane(decahydro-naphthalene),octahydro-indene(bicyclo[4.3.0]nonane), bicyclo[3.3.1]nonane,bicyclo[3.2.1]octane, spiro[4.5]decane, spiro[3.5]nonane, norbornane,adamantane, bicyclo[1.1.0]butane, spiro[2.2]pentane,bicyclo[2.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane,nortricyclane, quadricyclane, bicyclo[3.3.0]octane,bicyclo[2.2.2]octane, perhydroquinacene, bicyclo[3.3.3]undecane andperhydroanthracene.

[0135] The “bicyclic 7- to 12-membered hydrocarbon cycle” is preferablybicyclo[4.4.0]decane(decahydro-naphthalene),octahydro-indene(bicyclo[4.3.0]nonane), bicyclo[3.3.1]nonane,bicyclo[3.2.1]octane, spiro[5.4]decane or spiro[3.5]nonane, and morepreferably bicyclo[4.4.0]decane(decahydro-naphthalene) oroctahydro-indene(bicyclo[4.3.0]nonane).

[0136] The term “bicyclic 7- to 12-membered hydrocarbon ring group” usedthroughout the present specification refers to a monovalent groupderived by removing a hydrogen atom from any desired position of theaforementioned “bicyclic 7- to 12-membered hydrocarbon cycle”.

[0137] The term “bicyclic 7- to 12-membered non-aromatic heterocyclicgroup” used throughout the present specification refers to

[0138] [1] a bicyclic non-aromatic cyclic group,

[0139] [2] having 7 to 12 atoms in the ring of the cyclic group,

[0140] [3] containing 1 to 3 hetero atoms among the atoms of the ring ofthe cyclic group,

[0141] [4] optionally including 1 to 3 double bonds in the ring, and

[0142] [5] optionally including 1 to 3 carbonyl in the ring.

[0143] That is, a “bicyclic 7- to 12-membered non-aromatic heterocyclicgroup” is a monovalent derived from the aforementioned “bicyclic 7- to12-membered hydrocarbon cycle” by [1] replacing any 1 to 3 methine ormethylene in the ring with oxygen, sulfur, nitrogen or —NH—, and then[2] removing a hydrogen atom at any desired position of the ring.

[0144] The term “4- to 14-membered heterocyclic group” used throughoutthe present specification has 4 to 14 members and refers to

[0145] [1] a monocyclic, bicyclic or tricyclic heterocyclic group,

[0146] [2] having 4 to 14 atoms in the ring of the cyclic group,

[0147] [3] containing 1 to 3 hetero atoms among the atoms of the ring ofthe cyclic group,

[0148] [4] optionally including 1 to 3 double bonds in the ring, and

[0149] [5] optionally including 1 to 3 carbonyl in the ring.

[0150] Specifically, for example, it refers the aforementioned“monocyclic 4- to 8-membered non-aromatic heterocyclic group” or“bicyclic 7- to 12-membered non-aromatic heterocyclic group”.

[0151] The “4- to 14-membered heterocyclic group” is preferably a “4- to7-membered heterocyclic group” as defined below, and more preferablythere may be mentioned tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydropyranyl, dioxoranyl, pyrrolidin-2-onyl, dihydrofuran-2-onyland piperidinyl.

[0152] The term “4- to 7-membered heterocyclic group” used throughoutthe present specification refers to 4- to 7-membered heterocyclic groupsamong the groups referred by “4- to 14-membered heterocyclic group” asdefined above. Specifically, it refers to a monovalent group derived byremoving a hydrogen atom from any desired position of a ring representedby, for example, the formula:

[0153] (wherein X¹⁰ represents sulfur, oxygen or —NX¹² (wherein X¹²represents hydrogen or C₁₋₆ alkyl), X¹¹ represents methylene, sulfur,oxygen or —NX¹³ (wherein X¹³ represents hydrogen or C₁₋₆ alkyl), and srepresents an integer of 1-3), and preferably there may be mentionedtetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dioxoranyl,pyrrolidin-2-onyl, dihydrofuran-2-onyl and piperidinyl. The term“tetrahydrofuranyl” used throughout the present specification refers toa monovalent group derived by removing a hydrogen atom from any desiredposition of a tetrahydrofuran ring, and specifically there may bementioned tetrahydrofuran-2-yl and tetrahydrofuran-3-yl.

[0154] The term “tetrahydrothiophenyl” used throughout the presentspecification refers to a monovalent group derived by removing ahydrogen atom from any desired position of a tetrahydrothiophene ring,and specifically there may be mentioned tetrahydrothiophen-2-yl andtetrahydrothiophen-3-yl.

[0155] The term “tetrahydropyranyl” used throughout the presentspecification refers to a monovalent group derived by removing ahydrogen atom from any desired position of a tetrahydropyran ring, andspecifically there may be mentioned tetrahydropyran-2-yl,tetrahydropyran-3-yl and tetrahydropyran-4-yl.

[0156] The term “dioxolanyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a dioxolane ring, and specifically there may bementioned dioxolan-2-yl and dioxolan-4-yl.

[0157] The term “pyrrolidin-2-onyl” used throughout the presentspecification refers to a monovalent group derived by removing ahydrogen atom from any desired position of a pyrrolidin-2-one ring, andspecifically there may be mentioned pyrrolidin-2-on-1-yl,pyrrolidin-2-on-3-yl, pyrrolidin-2-on-4-yl and pyrrolidin-2-on-5-yl.

[0158] The term “furanyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a furan ring, and specifically there may bementioned 2-furanyl and 3-furanyl.

[0159] The term “thienyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a thiophene ring, and specifically there may bementioned 2-thienyl and 3-thienyl.

[0160] The term “pyrrolidinyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a pyrrolidine ring, and specifically there maybe mentioned 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl.

[0161] The term “piperidyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a piperidine ring, and specifically there may bementioned 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl.

[0162] The term “oxazolyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of an oxazole ring, and specifically there may bementioned 2-oxazolyl, 4-oxazolyl and 5-oxazolyl.

[0163] The term “isoxazolyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of an isoxazole ring, and specifically there may bementioned 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl.

[0164] The term “thiazolyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a thiazole ring, and specifically there may bementioned 2-thiazolyl, 4-thiazolyl and 5-thiazolyl.

[0165] The term “pyrrolyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a pyrrole ring, and specifically there may bementioned 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl.

[0166] The term “pyrazolyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a pyrazole ring, and specifically there may bementioned 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl and 5-pyrazolyl.

[0167] The term “morpholinyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a morpholine ring, and specifically there may bementioned 4-morpholinyl, 2-morpholinyl and 3-morpholinyl.

[0168] The term “pyridyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a pyridine ring, and specifically there may bementioned 2-pyridyl, 3-pyridyl and 4-pyridyl.

[0169] The term “dioxanyl” used throughout the present specificationrefers to a monovalent group derived by removing a hydrogen atom fromany desired position of a 1,3-dioxane ring or 1,4-dioxane ring, andspecifically there may be mentioned 1,3-dioxan-2-yl, 1,3-dioxan-4-yl,1,3-dioxan-5-yl and 1,4-dioxan-2-yl.

[0170] The term “dihydropyranyl” used throughout the presentspecification refers to a monovalent group derived by removing ahydrogen atom from any desired position of a 3,4-dihydro-2H-pyran ringor 3,6-dihydro-2H-pyran ring, and specifically there may be mentioned3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl,3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl,3,4-dihydro-2H-pyran-6-yl, 3,6-dihydro-2H-pyran-2-yl,3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl,3,6-dihydro-2H-pyran-5-yl and 3,6-dihydro-2H-pyran-6-yl.

[0171] The term “dihydrofuran-2-onyl” used throughout the presentspecification refers to a monovalent group derived by removing ahydrogen atom from any desired position of a dihydrofuran-2-one ring,and specifically there may be mentioned dihydrofuran-2-on-3-yl,dihydrofuran-2-on-4-yl and dihydrofuran-2-on-5-yl.

[0172] A compound of general formula (I) above wherein “R² and R³ or R³and R⁴ may bond together to form a 5- to 7-membered ring optionallycontaining 1 to 4 hetero atoms in the ring and optionally containingcarbonyl in the ring” is a compound in which the pyrazolo[1,5-a]pyridinein general formula (I) is fused with M¹ at the bonding positions of R²and R³, as represented by the formula:

[0173] (wherein R¹, R⁴, R⁵, R⁶ and Ar have the same definitions asabove, ring M¹ is a 5- to 7-membered ring optionally having 1 to 4hetero atoms and optionally having carbonyl in the ring, and ring M¹also optionally has a substituent selected from Substituent Group Aabove), or a compound in which the pyrazolo[1,5-a]pyridine in generalformula (I) is fused with Ml at the bonding positions of R⁴ and R³, asrepresented by the formula:

[0174] (wherein R¹, R², R⁵, R⁶ and Ar have the same definitions asabove, ring M¹ is a 5- to 7-membered ring optionally having 1 to 4hetero atoms and optionally having a carbonyl group in the ring, andring M¹ also optionally has a substituent selected from SubstituentGroup A above).

[0175] As rings for “ring M¹” there may be mentioned as preferablepyridine optionally having a substituent selected from Substituent GroupA, benzene optionally having a substituent selected from SubstituentGroup A, thiophene optionally having a substituent selected fromSubstituent Group A, cyclohexane optionally having a substituentselected from Substituent Group A, pyridine optionally having asubstituent selected from Substituent Group A and piperidin-2-oneoptionally having a substituent selected from Substituent Group A.

[0176] A compound of general formula (I) above wherein “R⁵ and R⁶ maybond together to form a 5- to 10-membered ring optionally containing 1to 4 hetero atoms in the ring and optionally containing carbonyl in thering” is a compound wherein R⁵ and R⁶ in formula (I) bond together toform ring M², as represented by the formula:

[0177] (wherein R¹, R², R³, R⁴ and Ar have the same definitions asabove, ring M2 is a 5- to 10-membered ring optionally having 1 to 4hetero atoms and optionally having carbonyl in the ring, and ring M²also optionally has a substituent selected from Substituent Group Aabove.

[0178] As rings for “ring M²” there may be mentioned as preferable “5-to 14-membered heteroaryl group” optionally having a substituentselected from Substituent Group A, “4- to 14-membered heterocyclicgroup” optionally having a substituent selected from Substituent GroupA, “9- to 11-membered benzene fused ring group” optionally having asubstituent selected from Substituent Group A, and “8- to 11-memberedheteroaryl fused ring group” optionally having a substituent selectedfrom Substituent Group A.

[0179] A compound of general formula (I) above wherein “R⁶ and R² maybond together to form a 6- to 7-membered ring optionally containing 1 or2 hetero atoms in the ring and optionally containing carbonyl in thering” is a compound wherein R⁶ and R² bond together as M³ to form aring, as represented by the formula:

[0180] (wherein R¹, R³, R⁴, R⁵ and Ar have the same definitions asabove, and M³ represents optionally substituted 1,2-ethylene, optionallysubstituted 1,3-propylene, optionally substituted 1,2-vinylene oroptionally substituted amide.

[0181] The term “salt” used throughout the present specification is notparticularly restricted so long as it is a salt formed with a compoundof the present invention and is pharmacologically acceptable, and aspreferred salts there may be mentioned hydrogen halide acid salt (forexample, hydrofluoride, hydrochloride, hydrobromide and hydroiodide),inorganic acid salt (for example, sulfate, nitrate, perchlorate,phosphate, carbonate and bicarbonate), organic carboxylate (for example,acetate, trifluoroacetate, oxalate, maleate, tartarate, fumarate andcitrate), organic sulfonate (for example, methanesulfonate,trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate and camphorsulfonate), amino acid salt (for example,aspartate and glutamate), quaternary amine salt, alkali metal salt (forexample, sodium salt and potassium salt) or alkaline earth metal salt(for example, magnesium salt and calcium salt), and more preferred as“pharmacologically acceptable salt” are hydrochloride, oxalate,trifluoroacetate and the like.

[0182] Representative production schemes for compounds represented byformula (I) above according to the invention will now be presented. Inthe following production schemes, R¹, R², R³, R⁴, R⁵, R⁶, R^(8a),R^(8b), R^(8c), R^(8d) and Ar have the same respective definitions givenabove, X represents halogen (for example, fluorine, chlorine, bromine oriodine), and X^(BS) represents boron substituted with OR^(8a) andOR^(8b) or tin substituted with R^(8c), R^(8d) and R^(8e). Y representsNR^(y), O, S(O)_(n), and A represents NO or NO₂. A group represented byProt^(N) is an amino protecting group, and a group represented byProt^(O) is a hydroxylprotecting group. A^(X) represents Ar or X [whereAr and X have the same respective definitions as given above], an Arring has the same definition for Ar given above, a Het ring representsan optionally substituted 5- to 14-membered heteroaryl or 9- to11-membered benzene fused ring group, and R^(1c) and R^(1d) eachrepresent optionally substituted C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl or the like. R^(ca) represents optionally substitutedC₁₋₆ alkyl or the like, and Lev represents a leaving group such ashalogen or trifluoromethanesulfonyl. R^(ar) and R^(het) each representcyano, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halogenated C₁₋₆ alkyl,C₁₋₆ alkoxy, halogenated C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₂₋₆ alkynyloxy,or the like. R^(rr) represents cyano, C₁₋₆ alkoxy, optionallysubstituted aryl or optionally substituted 5- to 14-membered heteroaryl,and R^(X1) represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,halogenated C₁₋₆ alkyl, benzyl, a substituent serving as a protectivegroup for a Y atom such as Boc, or the like. R_(y) and R^(6O) eachrepresent a substituent selected from Substituent Group A, n representsan integer of 0-2 and m represents an integer of 0-6. The term “roomtemperature” used below refers to a range of 0-40° C.

[0183] Step A: A halogenated compound (1) may be reacted in the presenceof a catalyst such as a palladium catalyst or copper (I) iodide, in thepresence of an acetylene derivative and a base and in an inert solventat 0-250° C., to obtain an acetylene derivative (2). The solvent usedwill differ depending on the starting material, reagent, etc. and is notparticularly restricted so long as it does not inhibit the reaction anddissolves the starting material to some extent, but preferably there maybe mentioned benzene, toluene, xylene, anisole, N,N-dimethylformamide,1,2-dimethoxyethane, tetrahydrofuran, dioxane, n-butanol, ethanol,methanol, 1-methyl-2-pyrrolidinone, water or mixtures thereof. The baseused will differ depending on the starting material, solvent, etc. andis not particularly restricted so long as it does not inhibit thereaction, and as preferred bases there may be mentioned potassiumcarbonate, sodium carbonate, cesium fluoride, potassium fluoride, sodiumhydrogencarbonate, triethylamine and diethylamine. These bases may alsobe used as solvents. When a palladium or nickel metal complex is used,its use will also differ depending on the starting material, solvent,etc. and is not particularly restricted so long as it does not inhibitthe reaction, but Pd(PPh₃)₄, Pd(OAc)₂/PPh₃, PdCl₂, PdCl₂(dppf),Ni(dpp)₂Cl₂ and the like are preferred.

[0184] Step B: The acetylene compound (2) may be treated with anN-amination agent (for example, hydroxylamine-O-sulfonic acid oro-mesitylenesulfonylhydroxylamine) in a solvent (for example, ethylacetate, tetrahydrofuran, diethyl ether, dichloromethane,1,2-dimethoxyethane, water, or the like) at a temperature of between−50° C. and room temperature to obtain an N-aminopyridinium salt, andthis may be reacted in the presence of a base at a temperature ofbetween 0° C. and 250° C. to obtain a closed ring compound (3). Thesolvent used will differ depending on the starting material, reagent,etc. and is not particularly restricted so long as it does not inhibitthe reaction and dissolves the starting material to some extent, butpreferably there may be mentioned benzene, toluene, xylene, anisole,N,N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran, dioxane,n-butanol, ethanol, methanol and 1-methyl-2-pyrrolidinone. The base usedwill differ depending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butas preferred bases there may be mentioned potassium carbonate, sodiumcarbonate, cesium fluoride, potassium fluoride, sodiumhydrogencarbonate, triethylamine, sodium methoxide, sodium ethoxide,sodium tert-butoxide and potassium tert-butoxide.

[0185] Step A: The pyrazolo[1,5-a]pyridine derivative (3) obtained inProduction Scheme 1 may be treated with an alkyllithium reagent (forexample, n-butyllithium, sec-butyllithium or tert-butyllithium) in aninert solvent at a temperature of between −78° C. and room temperatureand then reacted with a halogenating agent to obtain a 7-halogenatedcompound (4). The halogenating agent used will differ depending on thestarting material, solvent, etc. and is not particularly restricted solong as it does not inhibit the reaction, but preferably there may bementioned bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide,N-iodosuccinimide, hexachloroethane, 1,2-dibromoethane,1,2-dibromo-1,1,2,2-tetrachloroethane and 1,2-diiodoethane. The solventused will differ depending on the starting material, reagents, etc. andis not particularly restricted so long as it does not inhibit thereaction and dissolves the starting material to some extent, butpreferably there may be mentioned hexane, pentane, tetrahydrofuran anddiethyl ether.

[0186] Step B: The halogenated compound (4) may be reacted with aheteroaryl-boric acid or aryl-boric acid compound or an aryl-metalcompound (for example, a heteroaryl-tin compound or aryl-tin compound)and a palladium or nickel complex, at a temperature of between 0° C. and250° C., to obtain an aryl- or heteroaryl-substituted derivative (5).The solvent used will differ depending on the starting material,reagents, etc. and is not particularly restricted so long as it does notinhibit the reaction and dissolves the starting material to some extent,but preferably there may be mentioned benzene, toluene, xylene,mesitylene, anisole, N,N-dimethylformamide, 1,2-dimethoxyethane,tetrahydrofuran, 1,4-dioxane, n-butanol, ethanol, methanol,1-methyl-2-pyrrolidinone, water and mixtures thereof. The base used willdiffer depending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butas preferred bases there may be mentioned potassium carbonate, sodiumcarbonate, barium hydroxide, cesium fluoride, potassium fluoride, sodiumhydrogencarbonate and triethylamine. When a palladium or nickel complexis used, its use will also differ depending on the starting material,solvent, etc. and is not particularly restricted so long as it does notinhibit the reaction, but Pd(PPh₃)₄, Pd(OAc)₂/PPh₃, PdCl₂, PdCl₂(dppf),Ni(dpp)₂Cl₂ and the like are preferred.

[0187] Step C: The pyrazolo[1,5-a]pyridine derivative (5) may be reactedwith a nitrating agent either in a solvent or without a solvent, toobtain a 3-nitro-pyrazolo[1,5-a]pyridine derivative (6). The solvent, ifused, will differ depending on the starting material, reagent, etc. andis not particularly restricted so long as it does not inhibit thereaction and dissolves the starting material to some extent, butpreferably there may be mentioned acetic anhydride, acetic acid,sulfuric acid, trifluoroacetic anhydride, trifluoroacetic acid,acetonitrile, 1,2-dimethoxyethane and tetrahydrofuran. The nitratingagent used will differ depending on the starting material, solvent, etc.and is not particularly restricted so long as it does not inhibit thereaction, but preferably there may be mentioned copper nitratetrihydrate, nitric acid, fuming nitric acid, sodium nitrate, BF₄NO₂, NH₄⁺NO₃ ⁻, and the like. The reaction temperature will normally be from−50° C. to 200° C.

[0188] Alternatively, the pyrazolo[1,5-a]pyridine derivative (5) may bereacted with a nitrosating agent to obtain a3-nitroso-pyrazolo[1,5-a]pyridine derivative (6). This reaction may alsobe conducted either without a solvent or with a solvent, in which casethe solvent will differ depending on the starting material, reagent,etc. and is not particularly restricted so long as it does not inhibitthe reaction and dissolves the starting material to some extent, butpreferably there may be mentioned solvents such as acetic anhydride,acetic acid, hydrochloric acid, sulfuric acid, trifluoroaceticanhydride, trifluoroacetic acid, acetonitrile, 1,2-dimethoxyethane andthe like, or their mixtures with water or ethanol. The nitrosating agentused will differ depending on the starting material, solvent, etc. andis not particularly restricted so long as it does not inhibit thereaction, but preferably there may be mentioned sodium nitrite, BF₄NOand the like. The reaction temperature will normally be from −20° C. to200° C.

[0189] Step D: The nitro derivative or nitroso derivative (6) may bereacted with a metal (powder) either in the presence or in the absenceof an acid and either in a solvent or without a solvent, to obtain a3-aminopyrazolo[1,5-a]pyridine derivative (7). The reaction temperaturewill normally be from −10° C. to 150° C. The acid, if used, will differdepending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butpreferably there may be mentioned acetic acid, hydrochloric acid,sulfuric acid and the like. The solvent, if used, will differ dependingon the starting material, reagent, etc. and is not particularlyrestricted so long as it does not inhibit the reaction and dissolves thestarting material to some extent, but preferably there may be mentionedmethanol, ethanol, n-butanol, water and the like, either alone ormixture thereof. The metal (powder) used may be Zn, Fe, SnCl₂, NiCl₂ orthe like.

[0190] As an alternative method, the nitro or nitroso derivative (6) maybe subjected to hydrogenation reaction under a hydrogen atmosphere toobtain a 3-amino-pyrazolo[1,5-a]pyridine derivative (7). The hydrogenpressure will normally be from 1 to 100 atmospheres, and the reactiontemperature from 0-200° C. The reaction may be conducted either withouta solvent or with a solvent, in which case the solvent will differdepending on the starting material, reagent, etc. and is notparticularly restricted so long as it does not inhibit the reaction anddissolves the starting material to some extent, but preferably there maybe mentioned methanol, ethanol, propanol, butanol, tetrahydrofuran,1,4-dioxane, ethyl acetate, acetone, N,N-dimethylformamide and the like.The reaction may be conducted either in the presence or in the absenceof an acid, and using a metal catalyst. The acid and metal catalyst usedwill differ depending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butas preferred acids there may be mentioned acetic acid and hydrochloricacid, while as preferred metal catalysts there may be mentioned Pd—C,PtO₂, Pt—C, Raney-Ni and the like. Also, ammonium formate or the likemay be heated in a solvent such as methanol to generate hydrogen in thesystem during the reaction to obtain a 3-aminopyrazolo[1,5-a]pyridinederivative (7).

[0191] Step E: The 3-aminopyrazolo[1,5-a]pyridine derivative (7) may bereacted with a carbonyl derivative (for example, diethylketone) or analdehyde derivative (for example, propionaldehyde) in the presence of areducing agent to obtain a pyrazolo[1,5-a]pyridine derivativerepresented by formula (I) or (I′). Compound (I) or compound (I′) may beobtained depending on the number of moles of the carbonyl derivative.The reaction may be conducted in the presence or in the absence of anacid, with or without a solvent, and in the presence or in the absenceof an inorganic salt. The solvent, if used, will differ depending on thestarting material, reagent, etc. and is not particularly restricted solong as it does not inhibit the reaction and dissolves the startingmaterials to some extent, but preferably there may be mentionedtetrahydrofuran, diethyl ether, 1,2-dichloroethane, dichloromethane,chloroform, acetonitrile, water and the like, which may be used alone oras mixed solvents. The acid, inorganic salt and reducing agent used willdiffer depending on the starting material, solvent, etc. and are notparticularly restricted so long as they do not inhibit the reaction, butpreferably there may be mentioned acetic acid, sulfuric acid and thelike as acids, sodium sulfate and the like as inorganic salts, andsodium triacetoxyborohydride, sodium borohydride, sodiumcyanoborohydride and the like as reducing agents. The reactiontemperature will normally be from −10° C. to 150° C.

[0192] Step A: The pyrazolo[1,5-a]pyridine derivative (4) may besubjected to nitration reaction or nitrosation reaction in the samemanner as Step C of Production Scheme 2 above, to obtain compound (8).

[0193] Step B: The halogenated compound (8) may be subjected tocross-coupling reaction in the same manner as Step B of ProductionScheme 2 above, to obtain an aryl- or heteroaryl-substituted derivative(6).

[0194] Step A: The 3-amino-pyrazolo[1,5-a]pyridine derivative (7) may bemay be subjected to reaction with an amino-protecting reagent (forexample, di-tert-butyl dicarbonate) to obtain a3-aminopyrazolo[1,5-a]pyridine derivative (9) having the 3-positionamino group protected with a carbamate group (for example,t-butoxycarbonyl). The reaction may be conducted with or without asolvent, and in the presence or in the absence of a base. The solvent,if used, will differ depending on the starting material, reagent, etc.and is not particularly restricted so long as it does not inhibit thereaction and dissolves the starting materials to some extent, butpreferably there may be mentioned tetrahydrofuran, diethyl ether,1,4-dioxane, dichloromethane, 1,2-dichloroethane, chloroform,N,N-dimethylformamide, and the like. The base, if used, will differdepending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butpreferably there may be mentioned triethylamine, sodium hydride,potassium carbonate, sodium carbonate, cesium carbonate, sodiumhydrogencarbonate, 4-(dimethylamino)pyridine, sodiumbis(trimethylsilyl)amide, and the like. The reaction temperature willnormally be from −70° C. to 150° C. As preferred examples of protectinggroups (“ProtN” in this scheme) there may be mentioned, in addition toBoc, also 9-fluorenylmethoxycarbonyl (Fmoc),2,2,2-trichloroethoxycarbonyl (Troc), and the like, in which case theamino group is protected using a reagent and reaction suitable for thatprotecting group.

[0195] Step B: The 3-aminopyrazolo[1,5-a]pyridine derivative (9) may bereacted with an alkylating agent (for example, an optionally substitutedalkyl halide), to obtain a pyrazolo[1,5-a]pyridine derivative (10). Thereaction may be conducted with or without a solvent, and in the presenceor in the absence of a base. The solvent, if used, will differ dependingon the starting material, reagent, etc. and is not particularlyrestricted so long as it does not inhibit the reaction and dissolves thestarting materials to some extent, but preferably there may be mentionedtetrahydrofuran, diethyl ether, N,N-dimethylformamide,dimethylsulfoxide, and the like. The base, if used, will differdepending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butpreferably there may be mentioned sodium hydride, potassium hydride,potassium carbonate, sodium carbonate, cesium carbonate, potassiumhydroxide, sodium hydroxide, and the like. The reaction temperature willnormally be from −70° C. to 200° C.

[0196] Step C: The amino group-protected 3-amino-pyrazolo[1,5-a]pyridinederivative (10) may be subjected to deprotecting reaction to obtain a3-monoalkylaminopyrazolo[1,5-a]pyridine derivative (I′). The reactionmay be conducted either in the presence or in the absence of adeprotecting reagent. If used, the deprotecting reagent will differdepending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butpreferably there may be mentioned hydrochloric acid, sulfuric acid,trifluoroacetic acid, methanesulfonic acid, iodotrimethylsilane,aluminum (III) chloride, trimethylsilyl triflate, and the like. When agroup other than Boc (such as Fmoc, Troc or the like) is used as theprotecting group, the deprotection is carried out using reagents andreaction suitable for that protecting group. The reaction may beconducted with or without a solvent, and if it is carried out with asolvent, the solvent is preferably ethyl acetate, tetrahydrofuran,diethyl ether, 1,4-dioxane, acetonitrile, dichloromethane, chloroform,nitromethane, phenol, anisole, thiophenol or the like. The solvent willdepend on the starting material, reagent, etc. and is not particularlyrestricted so long as it does not inhibit the reaction and dissolves thestarting materials to some extent. The reaction temperature willnormally be from −70° C. to 200° C.

[0197] Step D: The pyrazolo[1,5-a]pyridine derivative (I′) may bereacted with a carbonyl derivative (for example, diethylketone), analdehyde derivative (for example, propionaldehyde) or acarbonyl-equivalent compound (for example, ((1-ethoxycyclopropyl)oxy)trimethylsilane), in the presence of a reducing agent, to obtain apyrazolo[1,5-a]pyridine derivative (I). The reaction temperature willnormally be from −10° C. to 150° C. The reaction may be conducted in thepresence or in the absence of an acid, with or without a solvent, and inthe presence or in the absence of an inorganic salt. The solvent, ifused, will differ depending on the starting material, reagent, etc. andis not particularly restricted so long as it does not inhibit thereaction and dissolves the starting materials to some extent, butpreferably there may be mentioned tetrahydrofuran, diethyl ether,1,2-dichloroethane, dichloromethane, chloroform, acetonitrile, ethanol,methanol, water and the like, which may be used alone or as mixedsolvents. The acid, inorganic salt and reducing agent used will differdepending on the starting material, solvent, etc. and are notparticularly restricted so long as they do not inhibit the reaction, butpreferably there may be mentioned acetic acid, sulfuric acid and thelike as acids, sodium sulfate and the like as inorganic salts, andsodium triacetoxyborohydride, sodium borohydride, sodiumcyanoborohydride and the like as reducing agents.

[0198] Alternatively, the pyrazolo[1,5-a]pyridine derivative (I′) may bereacted with an acylating agent either in the presence or in the absenceof a base, and with or without a solvent, to obtain apyrazolo[1,5-a]pyridine derivative (I). The reaction temperature willnormally be from −20° C. to 150° C. The solvent, if used, will differdepending on the starting material, reagent, etc. and is notparticularly restricted so long as it does not inhibit the reaction anddissolves the starting materials to some extent, but preferably theremay be mentioned tetrahydrofuran, diethyl ether, 1,2-dichloroethane,dichloromethane, acetonitrile, ethanol, methanol, water and the like,which may be used alone or as mixed solvents. The base, if used, willdiffer depending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butpreferably there may be mentioned triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, and thelike.

[0199] Step A: The nitro derivative or nitroso derivative (8) may bereacted with a metal (powder) to obtain a 3-aminopyrazolo[1,5-a]pyridinederivative (11). The reaction temperature will normally be from −10° C.to 150° C. The reaction may be conducted either in the presence or inthe absence of an acid, and with or without a solvent. The acid, ifused, will differ depending on the starting material, solvent, etc. andis not particularly restricted so long as it does not inhibit thereaction, but preferably there may be mentioned acetic acid,hydrochloric acid, sulfuric acid, and the like. The solvent, if used,will differ depending on the starting material, reagents, etc. and isnot particularly restricted so long as it does not inhibit the reactionand dissolves the starting materials to some extent, but preferablythere may be mentioned methanol, ethanol, n-butanol, tetrahydrofuran,water and the like, which may be used alone or as mixed solvents. Themetal (powder) used may be zinc, iron, SnCl₂, NiCl₂, or the like.

[0200] Step B: The 3-aminopyrazolo[1,5-a]pyridine derivative (11) may besubjected to reaction in the same manner as Step A of Production Scheme4 above, and the amino group thereof protected, to obtain compound (12).

[0201] Step C: The halogenated compound (12) may be subjected tocross-coupling reaction using a palladium catalyst in the same manner asStep B of Production Scheme 2 above, to obtain compound (9).

[0202] Step A: A carboxylic acid derivative (13) and an azidating agent(for example, diphenylphosphoryl azide (DPPA)) may be reacted with orwithout a solvent and in the presence or in the absence of a base at atemperature from −70° C. to 250° C. to produce an acid azide derivative,and the acid azide derivative heated to 0-250° C. for rearrangementreaction, such as Curtius rearrangement reaction, to produce isocyanatein the system, and then subjected to reaction with t-butanol or thelike, to obtain a 3-aminopyrazolo[1,5-a]pyridine derivative ((9) or(12)) protected with a carbamate group such as t-butoxycarbonyl(Boc).The solvent, if used, will differ depending on the starting material,reagents, etc. and is not particularly restricted so long as it does notinhibit the reaction and dissolves the starting material to some extent,but preferably there may be mentioned benzene, toluene, xylene,diphenylether, t-butanol, tetrahydrofuran, dioxane, acetonitrile,N,N-dimethylformamide and the like, which may be used alone or as mixedsolvents. The base, if used, will differ depending on the startingmaterial, solvent, etc. and is not particularly restricted so long as itdoes not inhibit the reaction, but preferably there may be mentionedtriethylamine, diisopropylethylamine, 4-(dimethylamino)pyridine,pyridine, and the like. As an alternative method for synthesis of theacid azide derivative, the carboxylic acid derivative (9) may beconverted to an acid chloride or mixed acid anhydride and subjected toreaction with an azidating agent (for example, sodium azide,trimethylsilyl azide, etc.) to obtain the acid azide derivative. As yetalternative methods, the target compound ((9) or (12)) may also beobtained by Hofmann rearrangement or Schmidt rearrangement reaction.

[0203] Step A: Compound (12) may be alkylated in the same manner as StepB of Production Scheme 4 to obtain Compound (13).

[0204] Step B: Compound (13) may be deprotected of the protecting groupin the same manner as Step C of Production Scheme 4 to obtain Compound(14).

[0205] Step C: Compound (14) may be alkylated or acylated in the samemanner as Step D of Production Scheme 4 to obtain Compound (15).

[0206] Step C: Compound (11) may be alkylated in the same manner as StepE of Production Scheme 2 to obtain Compound (15).

[0207] Step E: Compound (15) may be cross-coupled using a palladiumcomplex or the like in the same manner as Step B of Production Scheme 2to obtain Compound (I).

[0208] Step A: Compound (19) was produced according to the methoddisclosed in Heterocycles, 1977, 6, 379. Specifically, Compound (17) maybe reacted with Compound (18)., to obtain Compound (19).

[0209] Step B: Compound (20) may be obtained by reduction of Compound(19) according to Step D of Production Scheme 2.

[0210] Step C: Compound (21) having the 3-position amino group protectedmay be obtained from Compound (20) according to Step A of ProductionScheme 4.

[0211] Step D: A halogenated compound (12′) may be obtained from the3-position amino group-protected Compound (21) by introducing a halogenat the 7-position according to Step A of Production Scheme 2.

[0212] Step A: Compound (I^(s)) may be oxidized using an oxidizing agentsuch as m-chloroperbenzoic acid or the like, either with or without asolvent, to obtain a sulfoxide (I^(s1)). The reaction temperature willnormally be from −70° C. to 150° C. The solvent, if used, will differdepending on the starting material, reagent, etc. and is notparticularly restricted so long as it does not inhibit the reaction anddissolves the starting material to some extent, but preferably there maybe mentioned acetone, acetic acid, trifluoroacetic acid,dichloromethane, chloroform, benzene, nitromethane, methanol, ethanol,water, and the like, which may be used alone or as mixed solvents. Asoxidizing agents to be used there may be mentioned m-chloroperbenzoicacid, trifluoroperacetic acid, bis(trimethylsilyl)peroxy acid, sodiumperiodate, dinitrogen tetroxide, nitric acid/sulfuric acid mixture,chromic acid, and the like.

[0213] Step B: The sulfoxide (I^(s1)) may be oxidized using an oxidizingagent such as m-chloroperbenzoic acid or the like, either with orwithout a solvent, to obtain a sulfone (I^(s2)). The reactiontemperature will normally be from −70° C. to 150° C. The solvent, ifused, will differ depending on the starting material, reagent, etc. andis not particularly restricted so long as it does not inhibit thereaction and dissolves the starting material to some extent, butpreferably there may be mentioned acetone, acetic acid, trifluoroaceticacid, dichloromethane, chloroform, benzene, methanol, ethanol, water,and the like, which may be used alone or as mixed solvents. As oxidizingagents to be used there may be mentioned m-chloroperbenzoic acid,chromic acid, osmium tetroxide, potassium permanganate, and the like.

[0214] Step A: A 2-pyridylacetic acid ester (22) andhydroxylamine-O-sulfonic acid (23) may be reacted in the presence or inthe absence of a base, and with a solvent, to obtain a2-hydroxypyrazolo[1,5-a]pyridine derivative (24). The reactiontemperature will normally be from 0° C. to 100° C. The solvent used willdiffer depending on the starting materials, reagent, etc. and is notparticularly restricted so long as it does not inhibit the reaction anddissolves the starting materials to some extent, but preferably theremay be mentioned acetone, acetic acid, methanol, ethanol, water, and thelike, which may be used alone or as mixed solvents.

[0215] Step B: A 2-hydroxypyrazolo[1,5-a]pyridine derivative (24) may bereacted with an alkylating agent either with or without a solvent, andin the presence or in the absence of a base, to obtain Compound (25).The reaction temperature will normally be from 0° C. to 100° C. Thesolvent, if used, will differ depending on the starting material,reagent, etc. and is not particularly restricted so long as it does notinhibit the reaction and dissolves the starting material to some extent,but preferably there may be mentioned acetone, methanol, ethanol, water,and the like, which may be used alone or as mixed solvents. Asalkylating agents there may be mentioned dimethylsulfuric acid, alkylhalides, diazomethane, trimethylsilyldiazomethane, or the like. Thebase, if used, will differ depending on the starting material, solvent,etc. and is not particularly restricted so long as it does not inhibitthe reaction, but preferably there may be mentioned calcium carbonate,sodium carbonate, sodium hydrogencarbonate, triethylamine, and the like.

[0216] Step C: Compound (25) may be used to obtain Compound (26) in thesame manner as Step A of Production Scheme 2.

[0217] Step D: Compound (26) may be used to obtain Compound (8′) in thesame manner as Step C of Production Scheme 2.

[0218] Step A: A step of converting the leaving group Lev substitutingat the 7-position or N atom at the 3-position of apyrazolo[1,5-a]pyridine derivative represented by formula (I^(a1)) orformula (I^(h1)), to a desired substituent R_(ar) or R^(rr). Thefollowing reactions may be employed.

[0219] [1] A pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a1)) or formula (I^(h1)) may be heated and reacted with a metalcyanide compound such as copper (I) cyanide, zinc cyanide or potassiumcyanide, either with or without a solvent and in the presence or in theabsence of a catalyst, to obtain a pyrazolo[1,5-a]pyridine derivativerepresented by formula (I^(a2)) or formula (I^(h2)). The reactiontemperature will normally be from 40° C. to 250° C. The solvent, ifused, will differ depending on the starting material, reagent, etc. andis not particularly restricted so long as it does not inhibit thereaction and dissolves the starting material to some extent, butpreferably there may be mentioned N,N-dimethylformamide,1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone,tetrahydrofuran, 1,4-dioxane, pyridine, quinoline, and the like, whichmay be used alone or as mixed solvents. The catalyst, if used, willdiffer depending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butpreferably there may be mentioned crown ethers such as 18-crown-6.

[0220] [2] A pyrazolo[1,5-a]pyridine derivative represented by formula(I^(a1)) or formula (I^(h1)) may be reacted with an organic boric acidderivative, an organic tin derivative or a metal cyanide compound suchas copper (I) cyanide, zinc cyanide or potassium cyanide, in thepresence of a palladium or nickel complex, either with or without asolvent and in the presence or in the absence of a base, to obtain apyrazolo[1,5-a]pyridine derivative represented by formula (I^(a2)) orformula (I^(h2)). The reaction temperature will normally be from 0° C.to 150° C. The solvent, if used, will differ depending on the startingmaterial, reagent, etc. and is not particularly restricted so long as itdoes not inhibit the reaction and dissolves the starting material tosome extent, but preferably there may be mentionedN,N-dimethylformamide, 1-methyl-2-pyrrolidinone,1,3-dimethyl-2-imidazolidinone, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, benzene, toluene, xylene, ethanol, water, and thelike, which may be used alone or as mixed solvents. As examples ofpalladium or nickel complexes to be used there may be mentionedPd(PPh₃)₄, Pd(OAc)₂/PPh₃, Pd₂(dba)₃, PdCl₂, PdCl₂(dppf), Ni(dpp)₂Cl₂,and the like. The base, if used, will differ depending on the startingmaterial, solvent, etc. and is not particularly restricted so long as itdoes not inhibit the reaction, but preferably there may be mentionedpotassium carbonate, sodium carbonate, cesium fluoride, potassiumfluoride, sodium hydrogencarbonate, barium hydroxide, triethylamine, andthe like.

[0221] Step A: A step of removing R^(x1) from a compound represented byformula (I^(a3)) having YR^(x1), wherein R^(x1) is considered to be aprotecting group, under conditions for its deprotection. For example,when YR^(x1) is a C₁₋₆ alkoxy group, it may be reacted with adeprotecting reagent such as boron tribromide, either with or without asolvent, to obtain a compound represented by formula (I^(a4)). Thereaction may be conducted either in the presence or in the absence of adeprotecting agent. The deprotecting agent, if used, will differdepending on the starting material, reagent, etc., and preferably theremay be mentioned boron tribromide, iodotrimethylsilane, borontrifluoride diethyl etherate, hydrochloric acid, and the like. Thesolvent used will differ depending on the starting material, reagent,etc. and is not particularly restricted so long as it does not inhibitthe reaction and dissolves the starting material to some extent, butpreferably there may be mentioned chloroform, dichloromethane,acetonitrile, ethyl acetate, methanol, ethanol, water, and the like,which may be used alone or as mixed solvents.

[0222] This step also includes deprotection of R^(x1) considered as aprotecting group when Y is NR_(y) or S(O)_(n).

[0223] Step B: For example, a compound represented by formula (I^(a4))having a phenolic hydroxyl group may be reacted with an alkylating agent(for example, an optionally substituted alkyl halide), either in thepresence or in the absence of a base, and with or without a solvent, toobtain a compound represented by formula (I^(a5)) having R_(y)introduced therein. The reaction is conducted either with or without asolvent, and in the presence or in the absence of a base. The solvent,if used, will differ depending on the starting material, reagent, etc.and is not particularly restricted so long as it does not inhibit thereaction and dissolves the starting material to some extent, butpreferably there may be mentioned tetrahydrofuran, diethyl ether,N,N-dimethylformamide, dimethylsulfoxide, acetone, ethanol, methanol,water, and the like. The base, if used, will differ depending on thestarting material, solvent, etc. and is not particularly restricted solong as it does not inhibit the reaction, but preferably there may bementioned sodium hydride, potassium hydride, potassium carbonate, sodiumcarbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, andthe like. The reaction temperature will normally be from −70° C. to 200°C.

[0224] As an alternative method, an optionally substituted alcoholderivative may be used for Mitsunobu reaction in the presence of a diazocompound such as diethyl azodicarboxylate and an organic phosphoruscompound such as triphenylphosphine, with or without a solvent, at areaction temperature of from −70° C. to 100° C., to obtain a compoundrepresented by formula (I^(a5)) having R_(y) introduced therein. Thesolvent, if used, will differ depending on the starting material,reagent, etc. and is not particularly restricted so long as it does notinhibit the reaction and dissolves the starting material to some extent,but preferably there may be mentioned tetrahydrofuran, diethyl ether,and the like.

[0225] The step may also include introduction of substituents bysuitable substituent-introduction methods when Y is NR_(y) or S(O)_(n).

[0226] Step A: Compound (I^(O)) having a hydroxyl group protected with abenzoate group or the like, on substituent R_(6O) on N atom at the3-position may be subjected to deprotecting reaction to obtain Compound(I^(O1)) having a hydroxyl group on the substituent R^(6O) on N atom atthe 3-position. The reaction may be conducted either in the presence orin the absence of a deprotecting agent. The deprotecting agent, if used,will differ depending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butpreferably there may be mentioned sodium hydroxide, potassium hydroxide,sodium hydrogencarbonate, potassium carbonate, sodium carbonate, and thelike. The reaction may also be conducted without or with a solvent, inwhich case the solvent is not particularly restricted so long as it doesnot inhibit the reaction and dissolves the starting material to someextent, but preferably there may be mentioned methanol, ethanol,n-butanol, water, and the like. The reaction temperature will normallybe from 0° C. to 200° C. When a group other than a benzoate group (forexample, methoxymethyl, benzyl, acetyl, etc.) is used as the protectinggroup, deprotection is carried out by reaction using a reagent suitedfor that protecting group.

[0227] Step A: Compound (12) or (15) may be reacted with a boric acidester derivative such as triethoxyborane or a halogenated organic tincompound such as trimethyltin chloride, either with or without asolvent, after using an organic lithium reagent such as n-butyllithiumto convert the halogen atom to an anion, to obtain an organic boric acidderivative or organic tin derivative represented by formula (27) or(28). The reaction temperature will normally be from −100° C. to roomtemperature. The solvent used will differ depending on the startingmaterial, reagent, etc. and is not particularly restricted so long as itdoes not inhibit the reaction and dissolves the starting material tosome extent, but preferably there may be mentioned tetrahydrofuran,diethyl ether, n-hexane, n-pentane, and mixtures thereof. The organiclithium reagent used will differ depending on the starting material orsolvent, but preferably there may be mentioned n-butyllithium,sec-butyllithium, tert-butyllithium, and the like. The boric acid esterused will also differ depending on the starting material, solvent, etc.,but preferably there may be mentioned trimethoxyborane, triethoxyborane,triisopropyloxyborane, and the like. The organic tin compound used willlikewise differ depending on the starting material, solvent, etc., butpreferably there may be mentioned trimethyltin chloride, tributyltinchloride, tributyltin bromide, and the like. Instead of using an organiclithium reagent, the organic boric acid derivative or organic tinderivative represented by formula (27) or (28) may be obtained by thereaction of a Grignard reagent, which is converted from the halide byusing metallic magnesium, and a boric acid ester, diborane compound or ahalogenated organic tin reagent, either with or without a solvent.

[0228] As an alternative method, Compound (12) or (15) may be subjectedto coupling reaction with a diborane such as bis(pinacolato)diborane oran organic tin compound such as hexamethylditin (IV), in the presence ofa Pd catalyst such as tetrakis(triphenylphosphine)palladium (0) complex,in the presence or in the absence of a base and with or without asolvent, to obtain an organic boric acid derivative or organic tinderivative represented by formula (27) or (28). The reaction temperaturewill normally be from 0° C. to 200° C. The solvent used will differdepending on the starting material, reagent, etc. and is notparticularly restricted so long as it does not inhibit the reaction anddissolves the starting material to some extent, but preferably there maybe mentioned dioxane, toluene, 1,2-dimethoxyethane, and mixturesthereof.

[0229] Step B: Compound (27) or (28) may be subjected to couplingreaction in the same manner as Step B of Production Scheme 2 above, toobtain Compound (9) or (I).

[0230] Step A: A pyrazolo[1,5-a]pyridine derivative (I′) may be reactedwith an aryl halide (for example, bromobenzene) or a heteroaryl halide(for example, 2-bromopyridine), in the presence or in the absence of anorganic phosphorus compound such as tri-t-butylphosphine, and in thepresence of a Pd catalyst such as Pd₂(dba)₃, to obtain apyrazolo[1,5-a]pyridine derivative (I) wherein R₆ is an aryl orheteroaryl group. The reaction temperature will normally be from 0° C.to 250° C. The reaction may be conducted in the presence or in theabsence of a base, and with or without a solvent. The solvent, if used,will differ depending on the starting material, reagent, etc. and is notparticularly restricted so long as it does not inhibit the reaction anddissolves the starting material to some extent, but preferably there maybe mentioned toluene, xylene, mesitylene, tetrahydrofuran, diethylether, 1,2-dimethoxyethane, 1,4-dioxane, water, and the like, which maybe used alone or as mixed solvents. The base, if used, will differdepending on the starting material, solvent, etc. and is notparticularly restricted so long as it does not inhibit the reaction, butpreferably there may be mentioned sodium t-butoxide, potassiumt-butoxide, sodium carbonate, potassium carbonate, barium carbonate,cesium carbonate, and the like. As organic phosphorus compounds to beused there may be mentioned tri-t-butylphosphine,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,di-t-butyl-o-biphenylphosphine, and the like. As Pd catalysts to be usedthere may be mentioned dichlorobis(tri-o-tolylphosphine)palladiumcomplex, tetrakis(triphenylphosphine)palladium complex, Pd₂(dba)₃,Pd₂(dba)₃CHCl₃, Pd(OAc)₂, PdCl₂(PPh₃)₂, and the like.

[0231] Representative production schemes for compound (I) according tothe present invention have been described above, but the startingcompounds and reagents used for production of the compounds of theinvention may also form salts or hydrates which will differ depending onthe starting materials and solvent used, and these are not particularlyrestricted so long as the reaction is not inhibited. The solvents usedwill also differ depending on the starting materials and reagents, andthey are not particularly restricted so long as they do not inhibit thereaction and dissolve the starting materials to some extent. Whencompound (I) of the present invention is obtained as a free compound, acommon method may be used to convert it to a salt which compound (I) canform. The different isomers (for example, geometric isomers, and opticalisomers, rotational isomers, stereoisomers and tautomers based onasymmetric carbons) obtained for compound (I) according to the inventionmay be purified and isolated using common separation means such asrecrystallization, diastereomer salt methods, enzymatic separationmethods and chromatography methods (for example, thin-layerchromatography, column chromatography, gas chromatography, etc.).

[0232] The compounds of the present invention represented by the formula(I) and their salts exhibit excellent antagonism against CRF receptorsand particularly CRF1 receptor, as well as low toxicity and high safety,and are therefore highly useful as drugs. The compounds of the inventionand their salts may therefore be used to obtain Corticotropin-ReleasingFactor (CRF) receptor antagonists and Corticotropin-Releasing Factor(CRF)-1 receptor or Corticotropin-Releasing Factor (CRF)-1 receptorantagonists.

[0233] The compounds of the present invention and their salts may beused to obtain pharmaceutical compositions (formulations) as (i)therapeutic or prophylactic agents for diseases associated withCorticotropin-Releasing Factor (CRF), (ii) therapeutic or prophylacticagents for depression, depressive symptom, mania, anxiety, generalizedanxiety disorder, panic disorder, phobias, obsessive-compulsivedisorder, posttraumatic stress disorder, Tourrete's syndrome, autism,affective disorder, dysthymia, bipolar disorder, cyclothymic personalityand schizophrenia, (iii) therapeutic or prophylactic agents fordepressive symptoms such as major depression, single-episode depression,recurrent depression, depression-induced child abuse or postpartumdepression, (iv) therapeutic or prophylactic agents for peptic ulcer,irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea,constipation, postoperative ileus, stress-associated gastrointestinaldisorders and nervous vomiting, and (v) therapeutic or prophylacticagents for Alzheimer's disease, senile dementia of Alzheimer's type,neurodegenerative disease, multi-infarct dementia, senile dementia,anorexia nervosa, eating disorder, obesity, diabetes, alcoholdependence, pharmacophilia, drug withdrawal symptoms, alcohol withdrawalsymptoms, sleep diorder, insomnia, migraine, stress-induced headache,muscle contraction induced headache, ischemic neuronal damage,excitotoxic neuronal damage, stroke, progressive supranuclear palsy,amyotrophic lateral sclerosis, multiple sclerosis, muscular spasm,chronic fatigue syndrome, psychosocial dwarfism, epilepsy, head trauma,spinal cord injury, cheirospasm, spasmodic torticollis, cervicobrachialsyndrome, primary glaucoma, Meniere's syndrome, autonomic imbalance,alopecia, neurosis, hypertension, cardiovascular disorder, tachycardia,congestive heart failure, hyperventilation syndrome, bronchial asthma,apneusis, sudden infant death syndrome, inflammatory disorder, pain,allergosis, impotence, menopausal disorder, fertilization disorder,infertility, cancer, HIV infection-related immune dysfunction,stress-induced immune dysfunction, hemorrhagic stress, Cushing'ssyndrome, thyroid function disorder, encephalomyelitis, acromegaly,incontinence and osteoporosis.

[0234] Treatment or prevention of a disease associated withCorticotropin-Releasing Factor (CRF) receptors is also possible bysingle or multiple administration of a therapeutically effective dose ofa compound of the invention or salt thereof to a patient with thedisease associated with CRF receptors.

[0235] Compounds represented by formula (I) according to the presentinvention and salts thereof or hydrates of the foregoing may be useddirectly or in admixture with publicly known pharmaceutically acceptablecarriers, and formulated by common methods. As preferred dosage formsthere may be mentioned tablets, powders, fine particles, granules,coated tablets, capsules, syrups, lozenges, inhalants, suppositories,injections, ointments, eye salves, eye drops, nasal drops, ear drops,paps, lotions and the like. For the formulation there may be employedany commonly used excipients, binders, disintegrators, lubricants,coloring agents, corrective coatings, and if necessary, stabilizers,emulsifiers, absorbefacients, surfactants, pH adjustors, preservatives,antioxidants, or the like, in combination with various components thatare ordinarily used as starting materials for pharmaceuticalformulations.

[0236] As such components there may be mentioned animal and vegetableoils such as soybean oil, beef tallow and synthetic glycerides;hydrocarbons such as liquid paraffin, squalane and solid paraffin; esteroils such as octyldodecyl myristate and isopropyl myristate; higheralcohols such as cetostearyl alcohol and behenyl alcohol; siliconeresins; silicone oils; surfactants such as polyoxyethylene fatty acidesters, sorbitan fatty acid esters, glycerin fatty acid esters,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenatedcastor oil and polyoxyethylene-polyoxypropylene block copolymer;water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid,carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone andmethylcellulose; lower alcohols such as ethanol and isopropanol;polyhydric alcohols such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; sugars such as glucose and sucrose; inorganicpowders such as silicic anhydride, magnesium aluminum silicate andaluminum silicate; purified water, and the like. Examples of excipientswhich may be used include lactose, corn starch, white soft sugar,glucose, mannitol, sorbit, crystalline cellulose and silicon dioxide;examples of binders which may be used include polyvinyl alcohol,polyvinyl ether, methylcellulose, ethylcellulose, gum arabic,tragacanth, gelatin, shellac, hydroxypropylcellulose,hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polypropyleneglycol/polyoxyethylene block polymer and meglumine, calcium citrate,dextrin pectin and carboxymethylcellulose calcium; examples ofdisintegrators which may be used include starch, agar, gelatin powder,crystalline cellulose, calcium carbonate, sodium hydrogencarbonate,calcium citrate, dextrin, pectin and carboxymethylcellulose calcium;examples of lubricants which may be used include magnesium stearate,talc, polyethylene glycol, silica and hydrogenated vegetable oils;examples of coloring agents which may be used include any of thoseapproved for addition to drugs; examples of corrective coatings whichmay be used include cocoa powder, menthol, aromatic powders, mentha oil,borneol and powdered cinnamon; and examples of antioxidants which may beused include those approved for addition to drugs, such as ascorbic acidand alpha-tocopherol.

[0237] An oral formulation may be prepared by combining a compound ofthe present invention or salt thereof with an excipient, if necessaryadding a binder, disintegrator, lubricant, coloring agent, correctivecoating or the like, and forming a powder, fine particles, granules,tablets, coated tablets, capsules, etc. by a common method.

[0238] The tablets or granules may, of course, also be coated with asugar coating, gelatin coating or other type of suitable coating ifnecessary.

[0239] In the case of a liquid formulation such as syrup, injection, eyedrops or the like, a common method may be used for formulation with a pHadjustor, solubilizer, isotonizing agent or the like, as well as asolubilizing aid, stabilizer, buffering agent, suspending agent,antioxidant, etc. if necessary. In the case of a liquid formulation, itmay also be lyophilized, and an injection may be administeredintravenously, subcutaneously or intramuscularly. As preferred examplesof suspending agents there may be mentioned methyl cellulose,polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder,sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate andthe like; as preferred examples of solubilizing aids there may bementioned polyoxyethylene hydrogenated castor oil, polysorbate 80,nicotinamide, polyoxyethylene sorbitan monolaurate and the like; aspreferred examples of stabilizing agents there may be mentioned sodiumsulfite, sodium metasulfite, ether and the like; and as preferredexamples of preservatives there may be mentioned methyl paraoxybenzoate,ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol, andthe like.

[0240] There are no particular restrictions on the method of preparingan external agent, and any common method may be employed. The basematerials used may be any raw materials commonly employed in drugs,quasi drugs, cosmetics and the like, and as examples there may bementioned raw materials such as animal and vegetable oils, mineral oils,ester oils, waxes, higher alcohols, fatty acids, silicone oils,surfactants, phospholipids, alcohols, polyhydric alcohols, water-solublepolymers, clay minerals, purified water and the like, with addition ofpH adjustors, antioxidants, chelating agents, antiseptics andfungicides, coloring agents, aromas and the like if necessary. Also, ifnecessary, there may also be included differentiation-inducingcomponents, or other components such as circulation promoters,microbicides, antiphlogistic agents, cell activators, vitamins, aminoacids, humectants, keratolytic agents and the like.

[0241] Drug formulations comprising the compounds of the presentinvention and salts thereof or hydrates of the foregoing as effectiveingredients are useful for disease treatment or prevention in mammals(for example, humans, mice, rats, guinea pigs, rabbits, dogs, horses,monkeys, etc.), and especially for disease treatment or prevention inhumans.

[0242] Although the dosage of a drug according to the present inventionwill differ depending on the patient's severity of symptoms, age,gender, body weight, the dosage form, type of salt, drug sensitivity andspecific type of disease, etc., it will generally be from about 30 μg to10 g, preferably from 100 μg to 500 mg, more preferably from 100 μg to100 mg per day for adult humans in the case of oral administration orabout 1-3000 μg/kg and preferably about 3-1000 μg/kg in the case ofinjection, administered once or divided over several times a day.

EXAMPLES

[0243] The following production examples, examples and test examplesserve only for the purpose of illustration and are not intended to berestrictive on the compounds of the invention in any way. It will beapparent to those skilled in the art that various modifications may beadded beyond these examples and within the scope of the claims of theinvention in the present specification in order to maximize the effectof the invention, and such modifications are also encompassed within theclaims.

Production Example 1

[0244] 2-(1-Butynyl)pyridine

[0245] After dissolving 2-bromopyridine (50 g) in diethylamine (500 mL)and adding dichlorobis(triphenylphosphine)palladium (II) (2.2 g) andcopper iodide (0.3 g), the mixture was stirred at room temperature for 4hours while introducing 1-butyne (100 g) as a gas. After bubbling innitrogen, extraction was performed with ethyl acetate. The insolubleportion was filtered out with celite, and then the organic layer waswashed with water and brine. After drying over anhydrous magnesiumsulfate and filtration, the solvent was concentrated under reducedpressure, the residue was purified by silica gel column chromatography,and the title compound (35 g) was obtained from the n-hexane:ethylacetate (5:1) fraction as a brown oil.

[0246]¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, J=7.6 Hz, 3H), 2.45 (q, J=7.6Hz, 2H), 7.16-7.20 (m, 1H), 7.35-7.38 (m, 1H), 7.59-7.63 (m, 1H),8.53-8.54 (m, 1H).

Production Example 2

[0247] 2-Ethylpyrazolo[1,5-a]pyridine

[0248] After dissolving 2-(1-butynyl)pyridine (12.8 g) indichloromethane (60 mL), a solution of O-mesitylenesulfonylhydroxyamine(Reference document: Synthesis, 1997, 1) (20 g) in dichloromethane (132mL) was added dropwise while cooling on ice, and the mixture was stirredfor 30 minutes. Diethyl ether (2 L) was added to the reaction mixture toprecipitate crystals, which were collected by filtration and dried underreduced pressure to obtain N-amino-2-(1-butynyl)pyridiniummesitylenesulfonate (12.6 g) as colorless crystals.

[0249] A 6.1 g portion of the obtained N-amino-2-(1-butynyl)pyridiniummesitylenesulfonate was dissolved in tetrahydrofuran (600 mL), potassiumtert-butoxide (3.55 g) was added at room temperature, and the mixturewas vigorously stirred for 30 minutes. After adding ice water to thereaction mixture, extraction was performed with ethyl acetate. Theaqueous layer was again extracted with ethyl acetate, the insolubleportion was filtered with a celite filter, and the organic layers werecombined and washed with brine. After drying over anhydrous magnesiumsulfate and filtration, the solvent was concentrated under reducedpressure, the residue was purified by silica gel column chromatography,and the title compound (0.63 g) was obtained from the n-hexane:ethylacetate (10:1) fraction as a light yellow oil.

[0250]¹H NMR (400 MHz, CDCl₃) δ 1.36 (t, J=7.6 Hz, 3H), 2.86 (q, J=7.6Hz, 2H), 6.30 (s, 1H), 6.65 (ddd, J=1.6, 6.8, 6.8 Hz, 1H), 7.04 (ddd,J=1.2, 6.8, 8.8 Hz, 1H), 7.41 (ddd, J=1.2, 1.2, 8.8 Hz, 1H), 8.37 (ddd,J=1.2, 1.2, 6.8 Hz, 1H).

Production Example 3

[0251] 7-Bromo-2-ethylpyrazolo[1,5-a]pyridine

[0252] After dissolving 2-ethylpyrazolo[1,5-a]pyridine (80 mg) intetrahydrofuran (1 mL), an n-butyllithiumhexane solution (1.6 M; 0.58mL) was added dropwise at −78° C. under a nitrogen stream, and themixture was stirred for 30 minutes. A solution of1,2-dibromo-1,1,2,2-tetrachloroethane (196 mg) in tetrahydrofuran (0.5mL) was added to the reaction mixture, and stirring was continued for 30minutes. The temperature was increased to room temperature, water wasadded, extraction was performed with ethyl acetate and the organic layerwas washed with water and brine. After drying over anhydrous magnesiumsulfate and filtration, the solvent was concentrated under reducedpressure, the residue was purified by silica gel column chromatographyand the title compound (90 mg) was obtained from the n-hexane:ethylacetate (20:1) fraction as a light brown oil.

[0253]¹H NMR (400 MHz, CDCl₃) δ 1.36 (t, J=7.6 Hz, 3H), 2.93 (q, J=7.6Hz, 2H), 6.49 (s, 1H), 6.94 (dd, J=7.2, 8.4 Hz, 1H), 6.99 (dd, J=1.6,7.2 Hz, 1H), 7.44 (dd, J=1.6, 8.4 Hz, 1H).

Production Example 4

[0254] 7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridine

[0255] After dissolving 7-bromo-2-ethylpyrazolo[1,5-a]pyridine (300 mg)in ethanol (2 mL) and toluene (4 mL), 2,4-dichlorophenylboric acid (508mg), tetrakis(triphenylphosphine)palladium (0) complex (154 mg) and 2Maqueous sodium carbonate (1.33 mL) were added and the mixture was heatedand stirred at 80° C. for 3 hours under a nitrogen stream. Water wasadded to the reaction mixture, extraction was performed with ethylacetate and the organic layer was washed with brine. After drying overanhydrous magnesium sulfate and filtration, the solvent was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography, and the title compound (380 mg) was obtained from then-hexane:ethyl acetate (100:1) fraction as a light yellow oil.

[0256]¹H NMR (400 MHz, CDCl₃) δ 1.30 (t, J=7.6 Hz, 3H), 2.82 (q, J=7.6Hz, 2H), 6.42 (s, 1H), 6.64 (dd, J=1.6, 6.8 Hz, 1H), 7.12 (dd, J=6.8,8.8 Hz, 1H), 7.38 (dd, J=2.0, 8.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.51(dd, J=1.6, 8.8 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H).

Production Example 5

[0257] 7-(2,4-Dichlorophenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine

[0258] After dissolving7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridine (280 mg) inacetonitrile (20 mL), nitronium tetrafluoroborate (255 mg) was added 4times at 30 minute intervals while stirring on ice. The reaction mixturewas added to ice water, extraction was performed with ethyl acetate andthe extract was washed with water and brine. After drying over anhydrousmagnesium sulfate and filtration, the solvent was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography, and the title compound (115 mg) was obtained from then-hexane:ethyl acetate (20:1) fraction as yellow crystals.

[0259]¹H NMR (400 MHz, CDCl₃) δ 1.30 (t, J=7.6 Hz, 3H), 3.15 (q, J=7.6Hz, 2H), 7.07 (dd, J=1.6, 7.2 Hz, 1H), 7.43 (d, J=1.2 Hz, 1H), 7.60 (t,J=1.2 Hz, 1H), 7.70 (dd, J=7.2, 8.8 Hz, 1H), 8.44 (dd, J=1.6, 8.8 Hz,1H).

Production Example 6

[0260] 7-Bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine

[0261] After dissolving 7-bromo-2-ethylpyrazolo[1,5-a]pyridine (1.1 g)in acetonitrile (20 mL), nitronium tetrafluoroborate (1.3 g) was addedwhile stirring on ice, and stirring was continued for 30 minutes. Thereaction mixture was added to ice water, extraction was performed withethyl acetate and the extract was washed with water and brine. Afterdrying over anhydrous magnesium sulfate and filtration, the solvent wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography, and the title compound (670 mg) was obtainedfrom the n-hexane:ethyl acetate (10:1) fraction as yellow crystals.

[0262]¹H NMR (400 MHz, CDCl₃) δ 1.42 (t, J=7.6 Hz, 3H), 3.27 (q, J=7.6Hz, 2H), 7.39 (dd, J=1.2, 7.6 Hz, 1H), 7.50 (dd, J=7.6, 8.8 Hz, 1H),8.38 (dd, J=1.2, 8.8 Hz, 1H).

Production Example 7

[0263]7-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine

[0264] After dissolving 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine(100 mg) in 1,2-dimethoxyethane (6 mL) and water (1 mL),2-chloro-4-methoxyphenylboric acid (138 mg),tetrakis(triphenylphosphine)palladium (0) complex (86 mg) and bariumhydroxide octahydrate (233 mg) were added and the mixture was heated andstirred at 80° C. for 3 hours under a nitrogen stream. Water was addedto the reaction mixture, extraction was performed with ethyl acetate andthe extract was washed with saturated aqueous sodium hydrogencarbonateand brine, in that order. After drying over anhydrous magnesium sulfateand filtration, the solvent was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography, and the titlecompound (90 mg) was obtained from the n-hexane:ethyl acetate (30:1)fraction as yellow crystals.

[0265]¹H NMR (400 MHz, CDCl₃) δ 1.30 (t, J=7.6 Hz, 3H), 3.15 (q, J=7.6Hz, 2H), 3.90 (s, 3H), 6.96 (dd, J=2.4, 8.4 Hz, 1H), 7.07 (dd, J=1.6,7.2 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.68 (dd,J=7.2, 8.8 Hz, 1H), 8.40 (dd, J=1.6, 8.8 Hz, 1H).

Production Example 8

[0266] 2-Ethyl-4-methoxypyrazolo[1,5-a]pyridine

[0267] After adding dichlorobis(triphenylphosphine)palladium (II) (671mg) and copper iodide (91 mg) to a solution of 2-bromo-3-methoxypyridine(18.0 g) in diethylamine (250 mL), 1-butyne (15.5 g) was bubbled throughat room temperature, and the mixture was stirred for 20 hours. Uponcompletion of the reaction, the solvent was distilled off under reducedpressure. Water was added to the obtained residue, extraction wasperformed with ethyl acetate, the extract was washed with brine anddried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The obtained residue was subjected to silica gelcolumn chromatography (500 g), and 2-(1-butynyl)-4-methoxypyridine (10.0g) was obtained from the n-hexane:ethyl acetate (2:1) fraction as abrown oil.

[0268] To a solution of the obtained 2-(1-butynyl)-4-methoxypyridine(10.0 g) in dichloromethane (100 mL) there was added dropwise a solutionof O-mesitylenesulfonylhydroxyamine (16.0 g) in dichloromethane (100 mL)at 0° C., and the mixture was stirred for 1 hour. Diethyl ether (250 mL)was added to the reaction mixture, and the precipitated solid wassuction filtered and dried to obtainN-amino-2-(1-butynyl)-4-methoxypyridinium mesitylenesulfonate as a whitesalt (20.7 g).

[0269] Potassium tert-butoxide (11.1 g) was added to a solution ofN-amino-2-(1-butynyl)-4-methoxypyridinium mesitylenesulfonate (20.7 g)in tetrahydrofuran (300 mL) and N,N-dimethylformamide (15 mL), and themixture was stirred at room temperature for 1 hour. Water was addedwhile cooling on ice, extraction was performed with ethyl acetate, theextract was washed with brine and dried over magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue wassubjected to silica gel column chromatography (200 g), and the titlecompound (6.44 g) was obtained from the n-hexane:ethyl acetate (3:1)fraction as a yellow oil.

[0270]¹H NMR (400 MHz, CDCl₃) δ 1.35 (t, J=7.6 Hz, 3H), 2.84 (q, J=7.6Hz, 2H), 3.93 (s, 3H), 6.32 (d, J=7.7 Hz, 1H), 6.42 (s, 1H), 6.57 (t,J=7.5 Hz, 1H), 8.03 (dd, J=0.7, 7.0 Hz, 1H).

Production Example 9

[0271] 7-Bromo-2-ethyl-4-methoxypyrazolo[1,5-a]pyridine

[0272] n-Butyllithium (1.31 mL) was slowly added dropwise to a solutionof 2-ethyl-4-methoxypyrazolo[1,5-a]pyridine (303 mg) in tetrahydrofuran(15 mL) at −78° C. After stirring the mixture at −78° C. for 1 hour,1,2-dibromoethane (0.18 mL) was added and stirring was continued for 1hour. Saturated aqueous ammonium chloride was added, extraction wasperformed with ethyl acetate, the extract was washed with brine anddried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was subjected to silica gel columnchromatography (20 g), and the title compound (282 mg) was obtained fromthe n-hexane:ethyl acetate (5:1) fraction as a colorless oil.

[0273]¹H NMR (400 MHz, CDCl₃) δ 1.35 (t, J=7.7 Hz, 3H), 2.91 (q, J=7.7Hz, 2H), 3.93 (s, 3H), 6.28 (d, J=8.1 Hz, 1H), 6.61 (s, 1H), 6.85 (d,J=8.1 Hz, 1H)

Production Example 10

[0274] 7-Bromo-2-ethyl-4-methoxy-3-nitropyrazolo[1,5-a]pyridine

[0275] After adding nitronium tetrafluoroborate (176 mg) to a solutionof 7-bromo-2-ethyl-4-methoxypyrazolo[1,5-a]pyridine (282 mg) inacetonitrile (20 mL) at 0° C., the mixture was stirred for 20 minutes.Upon completion of the reaction, water was added, extraction wasperformed with ethyl acetate, the extract was washed with saturatedaqueous sodium hydrogencarbonate and brine and dried over magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was subjected to silica gel column chromatography (20 g), andthe title compound (159 mg) was obtained from the n-hexane:ethyl acetate(3:1) fraction as yellow crystals.

[0276]¹H NMR (400 MHz, CDCl₃) δ 1.39 (t, J=7.5 Hz, 3H), 3.13 (q, J=7.5Hz, 2H), 3.99 (s, 3H), 6.72 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H).

Production Example 11

[0277]2-Ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitropyrazolo[1,5-a]pyridine

[0278] After adding 4,6-dimethyl-2-methoxyphenylboric acid (191 mg),barium hydroxide octahydrate (334 mg) andtetrakis(triphenylphosphine)palladium (0) complex (123 mg) to a solutionof 7-bromo-2-ethyl-4-methoxy-3-nitropyrazolo[1,5-a]pyridine (159 mg) ina mixture of ethyleneglycol diethyl ether (15 mL) and water (7.5 mL),the mixture was heated at 80° C. for 30 minutes. Water was added,extraction was performed with ethyl acetate, the extract was washed withsaturated aqueous sodium hydrogencarbonate and brine and dried overmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was subjected to silica gel column chromatography(20 g), and the title compound (185 mg) was obtained from then-hexane:ethyl acetate (5:1) fraction as yellow crystals.

[0279]¹H NMR (400 MHz, CDCl₃) δ 1.24 (t, J=7.5 Hz, 3H), 1.98 (s, 3H),2.40 (s, 3H), 2.99 (q, J=7.5 Hz, 2H), 3.66 (s, 3H), 4.03 (s, 3H), 6.68(s, 1H), 6.78 (s, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H).

Production Example 12

[0280] tert-Butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate

[0281] 2-Methylthio-3-nitropyrazolo[1,5-a]pyridine (Reference document:Heterocycles, 1977, 6, 379) (400 mg) was suspended in ethanol (20 mL),and then water (10 mL), acetic acid (2 mL) and zinc powder (800 mg) wereadded and the mixture was heated and stirred at 80° C. for 30 minutes.The reaction mixture was filtered, water was added to the filtrate,extraction was performed with ethyl acetate and the extract was washedwith saturated aqueous sodium hydrogencarbonate and brine. After dryingover anhydrous magnesium sulfate and filtration, the solvent wasconcentrated under reduced pressure to obtain2-methylthiopyrazolo[1,5-a]pyridin-3-yl]amine as a crude product. Thiswas then dissolved in dichloromethane (5 mL), triethylamine (0.4 mL) wasadded, di-tert-butyl dicarbonate (625 mg) was further added whilecooling on ice, and the mixture was stirred overnight at roomtemperature. After adding water to the reaction mixture, extraction wasperformed twice with ethyl acetate and the organic layer was washed withwater and brine. After drying over anhydrous magnesium sulfate andfiltration, the solvent was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography, and the titlecompound (230 mg) was obtained from the n-hexane:ethyl acetate (5:1)fraction as a yellow oil.

[0282]¹H NMR (400 MHz, CDCl₃) δ 1.53 (br s, 9H), 2.60 (s, 3H), 6.00-6.15(m, 1H), 6.69 (t, J=6.8 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 7.40-7.50 (m,1H), 8.83 (d, J=6.8 Hz, 1H).

Production Example 13

[0283] tert-ButylN-[7-iodo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate

[0284] After dissolving tert-butylN-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (21.6 g) intetrahydrofuran (1 L), a solution of n-butyllithium in hexane (1.6 M;130 mL) was added dropwise at −78° C. under a nitrogen stream, and themixture was stirred for 30 minutes. A solution of 1,2-diiodoethane (24g) in tetrahydrofuran (50 mL) was added to the reaction mixture, andstirring was continued for 1 hour. Saturated aqueous ammonium chloridewas added to the reaction mixture, the temperature was raised to roomtemperature, extraction was performed with ethyl acetate and the extractwas washed with water and brine. After drying over anhydrous magnesiumsulfate and filtration, the solvent was concentrated under reducedpressure, the residue was purified by silica gel column chromatography,and the title compound was obtained from the n-hexane:ethyl acetate(5:1) fraction as yellow crystals.

[0285]¹H NMR (400 MHz, CDCl₃) δ 1.52 (s, 9H), 2.64 (s, 3H), 6.02-6.10(m, 1H), 6.81 (dd, J=7.2, 8.8 Hz, 1H), 7.22 (dd, J=1.2, 7.2 Hz, 1H),7.42-7.50 (m, 1H).

Production Example 14

[0286] 7-Bromo-2-methoxypyrazolo[1,5-a]pyridine

[0287] A solution of 2-methoxypyrazolo[1,5-a]pyridine (7.15 g) [CASNo.59942-88-0] in tetrahydrofuran (140 mL) was cooled to −78° C. under anitrogen stream, and then a solution of n-butyllithium in hexane (1.6 M;46 mL) was added dropwise and the mixture was stirred for 30 minutes. Asolution of 1,2-dibromo-1,1,2,2-tetrachloroethane (18.9 g) intetrahydrofuran (30 mL) was added dropwise at −78° C., and stirring wascontinued for 1 hour. After increasing the temperature of the reactionmixture to room temperature and adding water, extraction was performedwith ethyl acetate and the extract was washed with brine. After dryingthe obtained organic layer over anhydrous magnesium sulfate andfiltering it, the solvent was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography, and the titlecompound (7.1 g) was obtained from the n-hexane:ethyl acetate (50:1)fraction as a yellow oil.

[0288]¹H NMR (400 MHz, CDCl₃) δ 4.03 (s, 3H), 6.02 (s, 1H), 6.91-6.97(m, 2H), 7.31 (dd, J=2.4, 7.6 Hz, 1H).

Production Example 15

[0289]2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitrosopyrazolo[1,5-a]pyridine

[0290] After dissolving 7-bromo-2-methoxypyrazolo[1,5-a]pyridine (400mg) in acetic acid (4 mL), an aqueous solution (2 mL) containing sodiumnitrite (134 mg) was added and the mixture was stirred at roomtemperature for 30 minutes. The precipitated crystals were collected byfiltration and washed with water. After dissolving the obtained crude7-bromo-2-methoxy-3-nitrosopyrazolo[1,5-a]pyridine, without furtherpurification, in 1,2-dimethoxyethane (40 mL) and water (20 mL),4,6-dimethyl-2-methoxyphenylboric acid (475 mg),tetrakis(triphenylphosphine)palladium (0) complex (203 mg) and bariumhydroxide octahydrate (829 mg) were added and the mixture was heated andstirred at 80° C. for 1 hour. Water was added to the reaction mixture,extraction was performed with ethyl acetate, the organic layer waswashed with brine, dried over anhydrous magnesium sulfate and filtered,and the solvent was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography, and the titlecompound (200 mg) was obtained from the n-hexane:ethyl acetate (5:1)fraction as a brown oil.

[0291]¹H NMR (400 MHz, CDCl₃) δ 2.05 (s, 3H), 2.43 (s, 3H), 3.70 (s,3H), 4.20 (s, 3H), 6.70 (s, 1H), 6.79 (s, 1H), 6.08 (dd, J=1.6, 7.2 Hz,1H), 7.80 (dd, J=7.2, 8.4 Hz, 1H), 8.30 (dd, J=1.6, 8.4 Hz, 1H).

Production Example 16

[0292] 7-Bromo-2-methoxypyrazolo[1,5-a]pyridine-3-amine

[0293] After dissolving 7-bromo-2-methoxypyrazolo[1,5-a]pyridine (1 g)in acetic acid (10 mL), an aqueous solution (5 mL) containing sodiumnitrite (334 mg) was added and the mixture was stirred at roomtemperature for 20 minutes. After adding ethanol (60 mL) and water (30mL) to the reaction mixture, zinc powder (1 g) was added and the mixturewas heated and stirred at 60° C. for 30 minutes. The insoluble residuewas filtered out, water was added, and extraction was performed withethyl acetate. After washing the organic layer with brine, drying itover anhydrous magnesium sulfate and filtering it, the solvent wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography, and the title compound (750 mg) was obtainedfrom the n-hexane:ethyl acetate (3:1) fraction as brown crystals.

[0294]¹H NMR (400 MHz, CDCl₃) δ 4.13 (s, 3H), 6.78 (dd, J=1.6, 6.8 Hz,1H), 6.81 (dd, J=6.8, 8.4 Hz, 1H), 7.24 (dd, J=1.6, 8.4 Hz, 1H)

Production Example 17

[0295] tert-ButylN-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate

[0296] After dissolving 7-bromo-2-methoxypyrazolo[1,5-a]pyridine-3-amine(810 mg) in dichloromethane (20 mL), triethylamine (0.7 mL) was added,di-tert-butyl dicarbonate (923 μL) was further added while cooling onice, and the mixture was stirred overnight at room temperature. Afteradding water to the reaction mixture, extraction was performed withethyl acetate and the organic layer was washed with brine. After dryingover anhydrous magnesium sulfate and filtration, the solvent wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography, and the title compound (1.05 g) was obtainedfrom the n-hexane:ethyl acetate (10:1) fraction as yellow crystals.

[0297]¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 4.12 (s, 3H), 6.89 (dd,J=1.2, 7.6 Hz, 1H), 6.94 (dd, J=7.6, 8.8 Hz, 1H), 7.30-7.39 (m, 1H).

Production Example 18

[0298]3-[(tert-Butoxycarbonyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-ylboricAcid

[0299] After dissolving tert-butylN-(7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl)carbamate (200mg) in tetrahydrofuran (2 mL), the mixture was cooled to −78° C. andn-butyllithium (1.6 M; 0.66 mL) was added dropwise. The mixture wasstirred for 1-hour at the same temperature, triethoxyborane (109 μL) wasadded and the temperature was increased to room temperature. Saturatedaqueous ammonium chloride was added to the obtained reaction mixture,and extraction was performed with ethyl acetate. The obtained organiclayer was washed with brine and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure to obtain thetitle compound (106 mg) as grayish white crystals.

[0300]¹H NMR (400 MHz, CDCl₃) δ 1.53 (br s, 9H), 2.59 (s, 3H), 6.05 (brs, 1H), 6.66 (ddd, J=1.6, 1.6, 6.8 Hz, 1H), 7.04-7.12 (m, 1H), 7.44 (brs, 2H), 8.27 (ddd, J=1.6, 1.6, 7.2 Hz, 1H).

Example 1

[0301] tert-ButylN-[7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]carbamate

[0302] After dissolving[7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine (60 mg)and triethylamine (0.041 mL) in dichloromethane, di-tert-butyldicarbonate (71 mg) was added while cooling on ice, and the mixture wasstirred overnight at room temperature. Water was added to the reactionmixture, extraction was performed with ethyl acetate and the organiclayer was washed with water and brine. After drying over anhydrousmagnesium sulfate and filtration, the solvent was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography, and the title compound (59 mg) was obtained from then-hexane:ethyl acetate (10:1) fraction as a light yellow oil.

[0303]¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, J=7.6 Hz, 3H), 1.68 (s, 9H),2.79 (q, J=7.6 Hz, 2H), 6.70 (dd, J=1.6, 6.8 Hz, 1H), 7.20 (dd, J=6.8,8.8 Hz, 1H), 7.39 (dd, J=2.0, 8.4 Hz, 1H), 7.44-7.50 (m, 2H), 7.56 (d,J=2.0 Hz, 1H).

Example 2

[0304]N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0305] 7-(2,4-Dichlorophenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine(110 mg) was suspended in ethanol (6 mL), and then water (3 mL), aceticacid (1 mL) and zinc powder (220 mg) were added and the mixture washeated and stirred at 60° C. for 1 hour. The reaction mixture wasfiltered, water was added to the filtrate, extraction was performed withethyl acetate and the extract was washed with saturated aqueous sodiumhydrogencarbonate and brine. After drying over anhydrous magnesiumsulfate and filtration, the solvent was concentrated under reducedpressure to obtain[7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine (90 mg)as crude crystals. These were dissolved in tetrahydrofuran (1 mL), andafter adding propionaldehyde (0.059 mL) and 3 M aqueous sulfuric acid(0.294 mL), sodium borohydride (22.2 mg) was added in five portionswhile vigorously stirring on ice, and stirring was continued for 30minutes. Water was added to the reaction mixture, extraction wasperformed with diethyl ether and the extract was washed with saturatedsodium hydrogencarbonate and brine. After drying over anhydrousmagnesium sulfate and filtration, the solvent was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography, and the title compound (59 mg) was obtained from then-hexane:ethyl acetate (100:1) fraction as a yellow oil.

[0306]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.6 Hz, 6H), 1.23 (t, J=7.6Hz, 3H), 1.34-1.44 (m, 4H), 2.75 (q, J=7.6 Hz, 2H), 3.02 (t, J=7.2 Hz,4H), 6.57 (dd, J=1.2, 6.8 Hz, 1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 6.57(dd, J=2.0, 8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.51 (dd, J=1.2, 8.8Hz, 1H), 7.54 (d, J=2.0 Hz, 1H).

Example 3

[0307]N-[7-(2-Chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0308]7-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (5mg) was suspended in ethanol (2 mL), and then water (1 mL), acetic acid(0.5 mL) and zinc powder (10 mg) were added and the mixture was heatedand stirred at 80° C. for 30 minutes. The reaction mixture was filtered,water was added to the filtrate, extraction was performed with ethylacetate and the extract was washed with saturated aqueous sodiumhydrogencarbonate and brine. After drying over anhydrous magnesiumsulfate and filtration, the solvent was concentrated under reducedpressure to obtain[7-(2-chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amineas crude crystals. These were dissolved in tetrahydrofuran (1 mL)without further purification, and after adding propionaldehyde (0.015mL) and 3 M aqueous sulfuric acid (0.071 mL), sodium borohydride (5.4mg) was added in five portions while vigorously stirring on ice, andstirring was continued for 30 minutes. Water was added to the reactionmixture, extraction was performed with diethyl ether and the extract waswashed with saturated sodium hydrogencarbonate and brine. After dryingover anhydrous magnesium sulfate and filtration, the solvent wasconcentrated under reduced pressure and the residue was purified bypreparative TLC [n-hexane:ethyl acetate (5:1), Rf=0.5] to obtain thetitle compound (6 mg) as a light yellow oil.

[0309]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.6 Hz, 6H), 1.23 (t, J=7.6Hz, 3H), 1.34-1.44 (m, 4H), 2.76 (q, J=7.6 Hz, 2H), 3.02 (t, J=7.6 Hz,4H), 3.87 (s, 3H), 6.56 (dd, J=1.6, 6.4 Hz, 1H), 6.92 (dd, J=2.8, 8.6Hz, 1H), 6.99 (dd, J=6.4, 8.6 Hz, 1H), 7.06 (d, J=2.8 Hz, 1H), 7.32 (d,J=8.6 Hz, 1H), 7.45 (dd, J=1.6, 8.6 Hz, 1H).

[0310] The compounds of Examples 4 to 22 were synthesized according tothe production methods of Examples 1, 2 and 3.

Example 4

[0311]N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0312] (Light Yellow Crystals)

[0313]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.6 Hz, 6H), 1.19 (t, J=7.6Hz, 3H), 1.34-1.44 (m, 4H), 1.98 (s, 3H), 2.39 (s, 3H), 2.74 (q, J=7.6Hz, 2H), 3.02 (t, J=7.6 Hz, 4H), 3.68 (s, 3H), 6.49 (dd, J=1.2, 6.8 Hz,1H), 6.68 (s, 1H), 6.76 (s, 1H), 6.99 (dd, J=6.8, 8.8 Hz, 1H), 6.99 (dd,J=1.2, 8.8 Hz, 1H).

Example 5

[0314]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0315] (Light Yellow Oil)

[0316]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.6 Hz, 6H), 1.21 (t, J=7.6Hz, 3H), 1.34-1.44 (m, 4H), 2.43 (s, 3H), 2.74 (q, J=7.6 Hz, 2H), 3.01(t, J=7.6 Hz, 4H), 3.70 (s, 6H), 6.51 (s, 2H), 6.57 (dd, J=1.2, 6.8 Hz,1H), 6.99 (dd, J=6.8, 8.8 Hz, 1H), 6.99 (dd, J=1.2, 8.8 Hz, 1H).

Example 6

[0317]N-[7-(2,4-Dimethoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0318] (Light Yellow Oil)

[0319]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.6 Hz, 6H), 1.24 (t, J=7.6Hz, 3H), 1.34-1.44 (m, 4H), 2.75 (q, J=7.6 Hz, 2H), 3.01 (t, J=7.6 Hz,4H), 3.75 (s, 3H), 3.87 (s, 3H), 6.58-6.62 (m, 3H), 6.98 (dd, J=6.8, 9.2Hz, 1H), 7.42 (dd, J=1.6, 8.8 Hz, 1H), 7.49 (d, J=9.2 Hz, 1H)

Example 7

[0320]N-[2-Ethyl-7-(4-methoxy-2-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0321] (Light Yellow Oil)

[0322]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.6 Hz, 6H), 1.23 (t, J=7.6Hz, 3H), 1.34-1.44 (m, 4H), 2.10 (s, 3H), 2.75 (q, J=7.6 Hz, 2H), 3.01(t, J=7.6 Hz, 4H), 3.86 (s, 3H), 6.49 (dd, J=1.6, 6.8 Hz, 1H), 6.82 (dd,J=2.8, 8.4 Hz, 1H), 6.86 (d, J=2.8 Hz, 1H), 6.99 (dd, J=6.8, 8.8 Hz,1H), 7.32 (d, J=8.4 Hz, 1H), 7.45 (dd, J=1.6, 8.8 Hz, 1H).

Example 8

[0323]N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0324] (Colorless Crystals)

[0325]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 4H), 0.30-0.36 (m, 4H),0.80-0.90 (m, 2H), 1.22 (t, J=7.6 Hz, 4H), 1.97 (s, 3H), 2.39 (s, 3H),2.72-2.84 (m, 2H), 2.99 (d, J=6.4 Hz, 2H), 3.68 (s, 3H), 6.48 (dd,J=1.2, 6.8 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 6.99 (dd, J=6.8, 8.8 Hz,1H), 7.46 (dd, J=1.2, 8.8 Hz, 1H)

Example 9

[0326]N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(4-methoxy-2-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0327] (Yellow Oil)

[0328]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 4H), 0.30-0.38 (m, 4H),0.78-0.90 (m, 2H), 1.26 (t, J=7.5 Hz, 3H), 2.08 (s, 3H), 2.81 (q, J=7.5Hz, 2H), 3.00 (d, J=6.6 Hz, 4H), 3.86 (s, 3H), 6.49 (dd, J=1.4, 6.7 Hz,1H), 6.80-6.90 (m, 2H), 6.99 (dd, J=6.8, 9.0 Hz, 1H), 7.34 (d, J=8.2 Hz,1H), 7.48 (dd, J=1.4, 8.9 Hz, 1H).

[0329] MS(ESI) m/z 390 MH⁺

Example 10

[0330]N-[7-(4-Chloro-2-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[0331] (Yellow Oil)

[0332]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 4H), 0.30-0.37 (m, 4H),0.76-0.88 (m, 2H), 1.25 (t, J=7.5 Hz, 3H), 2.79 (q, J=7.5 Hz, 2H), 2.98(d, J=6.6 Hz, 4H), 3.75 (s, 3H), 6.57 (dd, J=1.3, 6.8 Hz, 1H), 6.97 (dd,J=6.8, 8.8 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 7.05 (dd, J=2.0, 8.1 Hz,1H), 7.46 (d, J=1.6 Hz, 1H), 7.48 (d, J=1.3 Hz, 1H).

[0333] MS(ESI) m/z 410 MH⁺

Example 11

[0334]N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0335] (Yellow Crystals)

[0336]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 4H), 0.30-0.40 (m, 4H),0.81-0.94 (m, 2H), 1.24 (t, J=7.5 Hz, 3H), 2.04 (s, 6H), 2.81 (q, J=7.5Hz, 2H), 3.03 (d, J=6.6 Hz, 4H), 3.87 (s, 3H), 6.45 (dd, J=1.5, 6.8 Hz,1H), 6.73 (s, 2H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.49 (dd, J=1.4, 8.9Hz, 1H)

[0337] MS(ESI) m/z 404 MH⁺

Example 12

[0338]N,N-Dicyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine

[0339] (Yellow Oil)

[0340]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.04 (m, 4H), 0.30-0.36 (m, 4H),0.80-0.90 (m, 2H), 1.23 (t, J=7.6 Hz, 3H), 2.43 (s, 3H), 2.78 (q, J=7.6Hz, 2H), 2.98 (d, J=6.8 Hz, 4H), 3.69 (s, 6H), 6.51 (s, 2H), 6.56 (dd,J=1.6, 6.8 Hz, 1H), 6.98 (dd, J=6.8, 8.8 Hz, 1H), 7.44 (dd, J=1.6, 8.8Hz, 1H)

Example 13

[0341]N,N-Dicyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine

[0342] (Colorless Crystals)

[0343]¹H NMR (400 MHz, CDCl₃) δ −0.02-−0.03 (m, 2H), 0.29-0.35 (m, 2H),0.80-0.90 (m, 1H), 1.23 (t, J=7.6 Hz, 3H), 2.00 (s, 3H), 2.74-2.84 (m,2H), 2.99 (d, J=6.4 Hz, 2H), 3.67 (s, 3H), 3.86 (s, 3H), 6.44 (d, J=2.0Hz, 1H), 6.47-6.50 (m, 2H), 6.98 (dd, J=6.8, 8.8 Hz, 1H), 7.45 (dd,J=1.6, 8.8 Hz, 1H).

Example 14

[0344]N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0345] (Light Yellow Crystals)

[0346]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.04 (m, 4H), 0.30-0.36 (m, 4H),0.80-0.90 (m, 2H), 1.23 (t, J=7.6 Hz, 3H), 2.79 (q, J=7.6 Hz, 2H), 2.99(d, J=6.8 Hz, 4H), 3.69 (s, 6H), 3.88 (s, 3H), 6.25 (s, 2H), 6.55 (dd,J=1.6, 6.8 Hz, 1H), 6.98 (dd, J=6.8, 8.8 Hz, 1H), 7.43 (dd, J=1.6, 8.8Hz, 1H).

Example 15

[0347]N,N-Dicyclopropylmethyl-N-[7-(2,4-dimethoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine

[0348] (Yellow Oil)

[0349]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.05 (m, 4H), 0.32-0.38 (m, 4H),0.80-0.90 (m, 2H), 1.26 (t, J=7.6 Hz, 3H), 2.80 (q, J=7.6 Hz, 2H), 2.98(d, J=6.8 Hz, 4H), 3.74 (s, 3H), 3.87 (s, 3H), 6.57-6.63 (m, 3H), 6.97(dd, J=6.8, 8.8 Hz, 1H), 7.44 (dd, J=1.6, 8.8 Hz, 1H), 7.48 (dd, J=1.2,7.6 Hz, 1H).

Example 16

[0350]N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0351] (Yellow Oil)

[0352]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.05 (m, 4H), 0.32-0.38 (m, 4H),0.80-0.90 (m, 2H), 1.26 (t, J=7.6 Hz, 3H), 2.43 (s, 3H), 2.80 (q, J=7.6Hz, 2H), 2.99 (d, J=6.8 Hz, 4H), 3.75 (s, 3H), 6.59 (dd, J=0.8, 6.8 Hz,1H), 6.86 (s, 1H), 6.89 (br d, J=7.6 Hz, 1H), 6.98 (dd, J=6.8, 8.8 Hz,1H), 7.41 (d, J=7.6 Hz, 1H), 7.45 (dd, J=0.8, 8.8 Hz, 1H)

Example 17

[0353]N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4-trifluoromethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0354] (Yellow Oil)

[0355]¹H NMR (400 MHz, CDCl₃) δ 0.01-0.06 (m, 4H), 0.32-0.37 (m, 4H),0.78-0.80 (m, 2H), 1.26 (t, J=7.6 Hz, 3H), 2.80 (q, J=7.6 Hz, 2H), 2.99(d, J=6.8 Hz, 4H), 3.81 (s, 3H), 6.61 (dd, J=1.2, 6.8 Hz, 1H), 7.00 (dd,J=6.8, 8.8 Hz, 1H), 7.24 (br s, 1H), 7.34 (br d J=7.6 Hz, 1H), 7.51 (dd,J=1.2, 8.8 Hz, 1H),7.65 (d, J=7.6 Hz, 1H).

Example 18

[0356]N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[0357] (Yellow Oil)

[0358]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 4H), 0.30-0.38 (m, 4H),0.78-0.91 (m, 2H), 1.23 (t, J=7.5 Hz, 3H), 2.79 (q, J=7.5 Hz, 2H), 2.99(d, J=6.6 Hz, 4H), 3.70 (s, 6H), 6.54 (dd, J=1.5, 6.8 Hz, 1H), 6.69 (s,2H), 6.98 (dd, J=6.8, 8.8 Hz, 1H), 7.46 (dd, J=1.5, 8.8 Hz, 1H)

[0359] MS(ESI) m/z 440 MH⁺

Example 19

[0360]N-[7-(2-Chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[0361] (Yellow Oil)

[0362]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 4H), 0.30-0.38 (m, 4H),0.77-0.90 (m, 2H), 1.26 (t, J=7.5 Hz, 3H), 2.80 (q, J=7.5 Hz, 2H), 2.99(d, J=6.6 Hz, 4H), 3.86 (s, 3H), 6.55 (dd, J=1.3, 6.8 Hz, 1H), 6.92 (dd,J=2.6, 8.6 Hz, 1H), 6.99 (dd, J=6.8, 9.0 Hz, 1H), 7.06 (d, J=2.4 Hz,1H), 7.47 (d, J=8.4 Hz, 1H), 7.49 (dd, J=1.3, 8.8 Hz, 1H).

[0363] MS(ESI) m/z 410 MH⁺

Example 20

[0364]N,N-Dicyclopropylmethyl-N-[7-(2,4-dichloro-6-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine

[0365] (White Crystals)

[0366]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 4H), 0.30-0.40 (m, 4H),0.79-0.92 (m, 2H), 1.24 (t, J=7.5 Hz, 3H), 2.80 (dq, J=2.2, 7.5 Hz, 2H),3.00 (d, J=6.8 Hz, 4H), 3.72 (s, 3H), 6.55 (dd, J=1.5, 6.8 Hz, 1H), 6.94(d, J=1.8 Hz, 1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H),7.52 (dd, J=1.4, 8.9 Hz, 1H).

[0367] MS(ESI) m/z 444 MH⁺

Example 21

[0368]N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(4-methoxy-2-trifluoromethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0369] (Yellow Oil)

[0370]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.03 (m, 4H), 0.30-0.36 (m, 4H),0.78-0.86 (m, 2H), 1.21 (t, J=7.6 Hz, 3H), 2.70-2.82(m, 2H, 2.98 (d,J=6.4 Hz, 4H), 3.91 (s, 3H), 6.49 (d, J=6.0 Hz, 1H), 6.98 (dd, J=6.8,8.8 Hz, 1H), 7.16 (dd, J=2.8, 8.8 Hz, 1H), 7.26-7.32 (m, 1H), 7.45-7.51(m, 2H)

Example 22

[0371]N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[0372] (Light Yellow Crystals)

[0373]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.04 (m, 4H), 0.32-0.36 (m, 4H),0.80-0.92 (m, 2H), 1.23 (t, J=8.0 Hz, 3H), 2.42 (s, 3H), 2.76-2.84 (m,2H), 3.00 (d, J=6.4 Hz, 4H), 3.70 (s, 3H), 6.55 (dd, J=1.6, 6.8 Hz, 1H),6.76 (br s, 1H), 6.98 (br s, 1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.50(dd, J=1.6, 8.8 Hz, 1H).

Example 23

[0374]N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-hexyl)amine

[0375] After dissolving[7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine (30 mg)in acetic acid (1 mL), 3-hexanone (0.024 mL) and sodium sulfate (139 mg)were added and the mixture was stirred at room temperature for 30minutes. Sodium triacetoxyborohydride (41.5 mg) was then added, andstirring was continued for 2 hours. Water was added to the reactionmixture, extraction was performed with ethyl acetate and the extract waswashed with saturated aqueous sodium hydrogencarbonate and brine. Afterdrying the obtained organic layer over anhydrous magnesium sulfate andfiltering it, the solvent was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography, and the titlecompound (21 mg) was obtained from the n-hexane:ethyl acetate (30:1)fraction as a yellow oil.

[0376]¹H NMR (400 MHz, CDCl₃) δ 0.86-0.93 (m, 3H), 0.97 (t, J=7.6 Hz,3H), 1.22-1.30 (m, 5H), 1.40-1.54 (m, 4H), 2.72-2.80 (m, 2H), 2.94-3.02(m, 1H), 6.54-6.60 (m, 1H), 6.98-7.06 (m, 1H), 7.25-7.27 (m, 1H), 7.36(dd, J=2.0, 8.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H).

Example 24

[0377]N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine

[0378] After dissolving tert-butylN-[7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]carbamate(57 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 7.3 mg)was added while cooling on ice, and then 2-bromoethyl methyl ether(0.015 mL) was added and the mixture was stirred for 1 hour. Water wasadded to the reaction mixture, extraction was performed with ethylacetate and the extract was washed with brine. The obtained organiclayer was dried over anhydrous magnesium sulfate and filtered, and thenthe solvent was concentrated under reduced pressure to obtain a crudeproduct. This was dissolved in ethyl acetate (1 mL) withoutpurification, a 4 N hydrochloric acid/ethyl acetate solution (2 mL) wasadded, and the mixture was stirred at room temperature for 1 hour. Thereaction mixture was neutralized with 5 N aqueous sodium hydroxide whilecooling on ice, and then extraction was performed with ethyl acetate andthe organic layer was washed with water and brine. After drying overanhydrous magnesium sulfate and filtration, the solvent was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography, and the title compound (46 mg) was obtained from then-hexane:ethyl acetate (5:1) fraction as a yellow oil.

[0379]¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, J=7.6 Hz, 3H), 2.77 (q, J=7.6Hz, 2H), 3.25 (t, J=4.8 Hz, 2H), 3.41 (s, 3H), 3.50 (t, J=4.8 Hz, 2H),6.57 (dd, J=1.6, 6.8 Hz, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.37 (dd,J=2.0, 8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.50-7.53 (m, 1H), 7.54 (d,J=2.0 Hz, 1H)

Example 25

[0380]N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)-N-propylamine

[0381]N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine(14 mg) was dissolved in tetrahydrofuran (1 mL), and after addingpropionaldehyde (0.016 mL) and 3 M aqueous sulfuric acid (0.77 mL),sodium borohydride (5.8 mg) was added in five portions while vigorouslystirring on ice, and stirring was continued for 30 minutes. Water wasadded to the reaction mixture, extraction was performed with diethylether and the extract was washed with saturated aqueous sodiumhydrogencarbonate and brine. After drying over anhydrous magnesiumsulfate and filtration, the solvent was concentrated under reducedpressure and the residue was purified by preparative TLC [n-hexane:ethylacetate (5:1), Rf=0.5] to obtain the title compound (9.5 mg) as a lightyellow oil.

[0382]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.6 Hz, 3H), 1.23 (t, J=7.6Hz, 3H), 1.34-1.44 (m, 2H), 2.75 (q, J=7.6 Hz, 2H), 3.08 (dd, J=6.4, 7.2Hz, 2H), 3.28 (t, J=6.0 Hz, 2H), 3.29 (s, 3H), 3.35 (t, J=6.0 Hz, 2H),6.59 (dd, J=1.6, 6.8 Hz, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.37 (dd,J=2.0, 8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.52 (dd, J=1.6, 8.8 Hz,1H), 7.54 (d, J=2.0 Hz, 1H).

[0383] The compounds of Examples 26 to 39 were synthesized according tothe production method of Example 25.

Example 26

[0384]N-Cyclopropylmethyl-N-[7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine

[0385] (Light Yellow Oil)

[0386]¹H NMR (400 MHz, CDCl₃) δ 0.01-0.03 (m, 2H), 0.34-0.38 (m, 2H),0.80-0.90 (m, 1H), 1.25 (t, J=7.6 Hz, 3H), 2.77 (q, J=7.6 Hz, 2H), 2.98(d, J=6.4 Hz, 2H), 3.29 (s, 3H), 3.37 (br s, 4H), 6.58 (dd, J=1.6, 6.8Hz, 1H), 7.03 (dd, J=6.8, 9.2 Hz, 1H), 7.38 (dd, J=2.0, 8.4 Hz, 1H),7.50 (d, J=8.4 Hz, 1H), 7.53 (dd, J=1.6, 9.2 Hz, 1H), 7.55 (d, J=2.0 Hz,1H).

Example 27

[0387]N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-isobutyl-N-(2-methoxyethyl)amine

[0388] (Light Yellow Oil)

[0389]¹H NMR (400 MHz, CDCl₃) δ 0.91 (d, J=6.8 Hz, 6H), 1.24 (t, J=7.6Hz, 3H), 1.52-1.62 (m, 1H), 2.76 (q, J=7.6 Hz, 2H), 2.92 (d, J=7.2 Hz,2H), 3.23 (t, J=6.0 Hz, 2H), 3.29 (s, 3H), 3.37 (t, J=6.0 Hz, 2H),6.57-6.60 (m, 1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.37 (dd, J=2.0, 8.4Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.52-7.55 (m, 1H), 7.54 (d, J=2.0 Hz,1H)

Example 28

[0390]N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isobutyl-N-(2-methoxyethyl)amine

[0391] (Light Yellow Oil)

[0392]¹H NMR (400 MHz, CDCl₃) δ 0.85-0.95 (m, 6H), 1.16-1.26 (m, 3H),1.52-1.62 (m, 1H), 1.97 (s, 3H), 2.39 (s, 3H), 2.70-2.80 (m, 2H),2.87-2.95 (m, 2H), 3.20-3.40 (m, 4H), 3.68 (s, 3H), 6.47-6.54 (m, 1H),6.69 (s, 1H), 6.77 (s, 1H), 6.98-7.06 (m, 1H), 7.42-7.50 (m, 1H).

Example 29

[0393]N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isobutyl-N-(2-methoxyethyl)amine

[0394] (Light Yellow Oil)

[0395] MS(ESI) m/z 396 MH⁺

Example 30

[0396]N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-propylamine

[0397] (Light Yellow Oil)

[0398]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.6 Hz, 3H), 1.20 (t, J=7.6Hz, 3H), 1.38-1.46 (m, 2H), 1.68-1.82 (m, 2H), 1.98 (s, 3H), 2.39 (s,3H), 2.73 (q, J=7.6 Hz, 2H), 3.00-3.05 (m, 2H), 3.22 (t, J=6.8 Hz, 2H),3.68 (s, 3H), 4.52 (td, J=6.0, 47.6 Hz, 2H), 6.52 (dd, J=1.6, 6.8 Hz,1H), 6.69 (s, 1H). 6.77 (s, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.42 (dd,J=1.6, 8.8 Hz, 1H).

Example 31

[0399]N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylmethylamine

[0400] (Light Yellow Oil)

[0401] MS(ESI) m/z 422 MH⁺

Example 32

[0402]N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

[0403] (Light Yellow Oil)

[0404] MS(ESI) m/z 392 MH⁺

Example 33

[0405]N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine

[0406] (Light Yellow Oil)

[0407] MS(ESI) m/z 408 MH⁺

Example 34

[0408]N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)amine

[0409] (Light Yellow Oil)

[0410]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.02 (m, 2H), 0.32-0.38 (m, 2H),0.80-0.90 (m, 2H), 1.20 (t, J=7.6 Hz, 3H), 1.70-1.82 (m, 2H), 1.97 (s,3H), 2.39 (s, 3H), 2.74 (q, J=7.6 Hz, 2H), 2.92 (d, J=6.8 Hz, 2H), 3.30(t, J=6.8 Hz, 2H), 3.68 (s, 3H), 4.55 (td, J=6.0, 47.2 Hz, 2H), 6.51(dd, J=1.2, 6.8 Hz, 1H), 6.69 (s, 1H). 6.77 (s, 1H), 7.02 (dd, J=6.8,8.8 Hz, 1H), 7.44 (dd, J=1.2, 8.8 Hz, 1H).

Example 35

[0411]N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

[0412] (Light Yellow Oil)

[0413] MS(ESI) m/z 434 MH⁺

Example 36

[0414]N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0415] (Yellow Oil)

[0416]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.03 (m, 2H), 0.33-0.40 (m, 2H),0.80-0.90 (m, 1H), 1.21 (t, J=7.2 Hz, 3H), 1.60-1.70 (m, 1H), 1.88-1.98(m, 1H), 1.99 (s, 3H), 2.23-2.32 (m, 1H), 2.40 (s, 3H), 2.76 (q, J=7.2Hz, 2H), 2.92 (d, J=6.4 Hz, 2H), 3.06-3.13 (m, 1H), 3.21-3.28 (m, 1H),3.60-3.65 (m, 1H), 3.66-3.72 (m, 4H), 3.73-3.86 (m, 2H), 6.52 (br d,J=6.8 Hz, 1H), 6.70 (s, 1H), 6.78 (s, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H),7.45 (br d, J=8.8 Hz, 1H).

Example 37

[0417]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0418] (Yellow Oil)

[0419]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.34-0.40 (m, 2H),0.80-0.90 (m, 1H), 1.21 (t, J=7.2 Hz, 3H), 1.55-1.67 (m, 1H), 1.86-1.96(m, 1H), 2.43 (s, 3H), 2.74 (q, J=7.2 Hz, 2H), 2.90 (d, J=6.8 Hz, 2H),3.04-3.11 (m, 1H), 3.20-3.26 (m, 1H), 3.58-3.84 (m, 7H), 6.51 (s, 2H),6.57-6.60 (m, 1H), 6.98-7.04 (m, 1H), 7.40-7.44 (m, 1H).

Example 38

[0420]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

[0421] (Light Yellow Oil)

[0422]¹H NMR (400 MHz, CDCl₃) δ −0.01-0.04 (m, 2H), 0.32-0.38 (m, 2H),0.80-0.90 (m, 1H), 1.22 (t, J=7.6 Hz, 3H), 1.62-1.70 (m, 1H), 1.75-1.95(m, 3H), 2.43 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 2.96 (d, J=6.8 Hz, 2H),3.03-3.10 (m, 1H), 3.40-3.46 (m, 1H), 3.64-3.72 (m, 4H), 3.80-3.90 (m,2H), 6.51 (s, 2H), 6.57 (dd, J=1.2, 6.8 Hz, 1H), 7.00 (dd, J=6.8, 8.8Hz, 1H), 7.46 (dd, J=1.2, 8.8 Hz, 1H).

Example 39

[0423]N-Cyclopropyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)amine

[0424] (Yellow Oil)

[0425]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.32-0.38 (m, 2H),0.80-0.90 (m, 1H), 1.22 (t, J=7.6 Hz, 3H), 2.41 (s, 3H), 2.77 (q, J=7.6Hz, 2H), 3.01 (d, J=7.2 Hz, 2H), 3.35 (d, J=4.4 Hz, 2H), 3.68 (s, 6H),3.78-3.84 (m, 2H), 3.94-3.98 (m, 2H), 4.90 (t, J=4.4 Hz, 1H), 6.49 (s,2H), 6.56 (dd, J=1.2, 6.8 Hz, 1H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.44(dd, J=1.2, 8.8 Hz, 1H).

Example 40

[0426]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0427] After dissolvingN-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine(150 mg) in 1,2-dimethoxyethane (20 mL) and water (10 mL),2,4-dimethoxy-6-methylphenylboric acid (155 mg),tetrakis(triphenylphosphine)palladium (0) complex (92 mg) and bariumhydroxide octahydrate (250 mg) were added and the mixture was heated andstirred at 80° C. for 1 hour. Water was added to the reaction mixture,extraction was performed with ethyl acetate, the organic layer waswashed with brine, dried over anhydrous magnesium sulfate and filtered,and the solvent was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography, and the titlecompound (88 mg) was obtained from the n-hexane:ethyl acetate (6:1)fraction as a yellow oil.

[0428]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.32-0.41 (m, 2H),0.80-0.92 (m, 1H), 1.23 (t, J=7.5 Hz, 3H), 1.58-1.70 (m, 1H), 1.87-2.00(m, 1H), 2.02 (s, 3H), 2.22-2.34 (m, 1H), 2.76 (dq, J=1.8, 7.5 Hz, 2H),2.92 (dd, J=1.7, 6.8 Hz, 2H), 3.06-3.14 (m, 1H), 3.20-3.29 (m, 1H),3.60-3.65 (m, 1H), 3.66-3.88 (m, 3H), 3.68 (s, 3H), 3.87 (s, 3H), 6.45(d, J=2.4 Hz, 1H), 6.49 (d, J=2.2 Hz, 1H), 6.52 (dd, J=0.9, 6.8 Hz, 1H),7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.42-7.48 (m, 1H).

[0429] The compounds of Examples 41 to 46 were synthesized according tothe production method of Example 40.

Example 41

[0430]N-Cyclopropylmethyl-N-[2-ethyl-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0431] (Yellow Crystals)

[0432]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.06 (m, 2H), 0.33-0.42 (m, 2H),0.80-0.92 (m, 1H), 1.23 (t, J=7.5 Hz, 3H), 1.60-1.73 (m, 1H), 1.90-2.02(m, 1H), 2.04 (s, 6H), 2.24-2.38 (m, 1H), 2.78 (q, J=7.5 Hz, 2H), 2.94(d, J=6.8 Hz, 2H), 3.13 (dd, J=8.6, 12.0 Hz, 1H), 3.27 (dd, J=6.6, 12.0Hz, 1H), 3.64 (dd, J=5.5, 8.6 Hz, 1H), 3.68-3.90 (m, 3H), 3.87 (s, 3H),6.48 (dd, J=1.3, 6.6 Hz, 1H), 6.74 (s, 2H), 7.05 (dd, J=6.6, 8.8 Hz,1H), 7.48 (dd, J=1.3, 8.8 Hz, 1H)

Example 42

[0433]N-[7-(4-Chloro-2-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine

[0434] (Light Brown Oil)

[0435]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.34-0.42 (m, 2H),0.78-0.90 (m, 1H), 1.25 (t, J=7.5 Hz, 3H), 1.58-1.69 (m, 1H), 1.85-1.96(m, 1H), 2.18-2.32 (m, 1H), 2.76 (q, J=7.5 Hz, 2H), 2.90 (d, J=6.8 Hz,2H), 3.08 (dd, J=8.6, 12.0 Hz, 1H), 3.23 (dd, J=6.8, 12.0 Hz, 1H),3.58-3.86 (m, 4H), 3.76 (s, 3H), 6.61 (dd, J=1.3, 6.8 Hz, 1H), 6.98-7.04(m, 2H), 7.06 (dd, J=1.9, 8.1 Hz, 1H), 7.45 (dd, J=1.3, 8.9 Hz, 1H),7.46 (d, J=8.1 Hz, 1H).

Example 43

[0436]N-Cyclopropylmethyl-N-[2-ethyl-7-(2-[2-(fluoromethoxy)-4,6-dimethylbenzyl]oxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0437] (Yellow Oil)

[0438]¹H NMR (400 MHz, CDCl₃) δ −0.08-0.02 (m, 2H), 0.28-0.36 (m, 2H),0.72-0.85 (m, 1H), 1.17 (t, J=7.5 Hz, 3H), 1.56-1.70 (m, 1H), 1.84-1.96(m, 1H), 1.88 (s, 3H), 1.96 (s, 3H), 2.23 (s, 3H), 2.16-2.26 (m, 1H),2.40 (s, 3H), 2.64-2.78 (m, 2H), 2.80-2.94 (m, 2H), 3.02-3.10 (m, 1H),3.14-3.25 (m, 1H), 3.56-3.86 (m, 4H), 4.87 (d, J=11.0 Hz, 1H), 5.03 (d,J=11.0 Hz, 1H), 5.38 (s, 1H), 5.52 (s, 1H), 6.42 (dd, J=1.4, 6.9 Hz,1H), 6.60 (s, 1H), 6.70 (s, 1H), 6.78 (s, 1H), 6.91 (s, 1H), 6.90-6.97(m, 1H), 7.37 (dd, J=1.3, 8.8 Hz, 1H).

Example 44

[0439]N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine

[0440] (Yellow Oil)

[0441]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.32-0.42 (m, 2H),0.78-0.92 (m, 1H), 1.22 (t, J=7.6 Hz, 3H), 1.58-1.70 (m, 1H), 1.86-1.98(m, 1H), 2.22-2.34 (m, 1H), 2.42 (s, 3H), 2.70-2.82 (m, 2H), 2.91 (dd,J=1.6, 6.8 Hz, 2H), 3.04-3.14 (m, 1H), 3.24 (dd, J=6.7, 12.0 Hz, 1H),3.59-3.87 (m, 4H), 3.70 (s, 3H), 6.58 (dd, J=1.3, 6.8 Hz, 1H), 6.75 (s,1H), 6.98 (s, 1H), 7.04 (dd, J=6.8, 8.9 Hz, 1H), 7.44-7.51 (m, 1H).

Example 45

[0442]N-Cyclopropylmethyl-N-2-ethyl-7-[2-(fluoromethoxy)-4,6-dimethylphenyl]pyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-3-furanylmethylamine

[0443] (Yellow Oil)

[0444]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.08 (m, 2H), 0.33-0.44 (m, 2H),0.80-0.94 (m, 1H), 1.23 (t, J=7.6 Hz, 3H), 1.60-1.74 (m, 1H), 1.89-2.01(m, 1H), 2.08 (s, 3H), 2.22-2.36 (m, 1H), 2.43 (s, 3H), 2.72-2.83 (m,2H), 2.93 (d, J=6.8 Hz, 2H), 3.08-3.16 (m, 1H), 3.22-3.31 (m, 1H),3.58-3.92 (m, 4H), 5.32 (d, J=2.6 Hz, 0.5H), 5.45 (d, J=2.7 Hz, 0.5H),5.54 (d, J=2.7 Hz, 0.5H), 5.68 (d, J=2.7 Hz, 0.5H), 6.56 (dd, J=1.3, 6.8Hz, 1H), 6.97 (s, 1H), 7.01 (s, 1H), 7.07 (dd, J=6.8, 8.8 Hz, 1H), 7.49(dd, J=1.3, 8.8 Hz, 1H).

Example 46

[0445]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

[0446] (Yellow Oil)

[0447]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.3 Hz, 3H), 1.21 (t, J=7.5Hz, 3H), 1.34-1.46 (m, 2H), 1.54-1.68 (m, 1H), 1.85-1.96 (m, 1H),2.18-2.32 (m, 1H), 2.43 (s, 3H), 2.73 (q, J=7.5 Hz, 2H), 2.94-3.05 (m,3H), 3.14 (dd, J=6.6, 12.0 Hz, 1H), 3.58 (dd, J=5.5, 8.4 Hz, 1H),3.62-3.85 (m, 3H), 3.69 (s, 6H), 6.51 (s, 2H), 6.59 (dd, J=1.5, 6.8 Hz,1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.40 (dd, J=1.3, 8.8 Hz, 1H)

[0448] MS(ESI) m/z 438 MH⁺

Example 47

[0449]N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[0450] After dissolvingN-cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine(255 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde(173 mg) [CAS No.50675-18-8] and sodium triacetoxyborohydride (241 mg)were added, and the mixture was stirred at room temperature for 1 hour.Saturated aqueous sodium hydrogencarbonate was added to the reactionmixture, extraction was performed with ethyl acetate, and the extractwas washed with brine. After drying over anhydrous magnesium sulfate andfiltration, the solvent was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography, and the titlecompound (134 mg) was obtained from the n-hexane:ethyl acetate (5:1)fraction as a yellow oil.

[0451]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.00 (m, 2H), 0.31-0.35 (m, 2H),0.76-0.88 (m, 1H), 1.20 (t, J=7.6 Hz, 3H), 1.24-1.34 (m, 2H), 1.54-1.65(m, 1H), 1.72-1.80 (m, 2H), 1.98 (s, 3H), 2.39 (s, 3H), 2.74 (dq, J=1.6,7.6 Hz, 2H), 2.88 (d, J=6.8 Hz, 2H), 3.04 (d, J=6.8 Hz, 2H), 3.31 (dt,J=2.0, 11.6 Hz, 2H), 3.68 (s., 3H), 3.92-3.98 (m, 2H), 6.51 (dd, J=1.6,6.8 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H),7.44 (dd, J=1.6, 8.8 Hz, 1H).

[0452] The compounds of Examples 48 to 61 were synthesized according tothe production method of Example 47.

Example 48

[0453]N-Cyclopropylmethyl-N-[2-ethyl-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0454] (White Crystals)

[0455]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.05 (m, 2H), 0.34-0.42 (m, 2H),0.78-0.90 (m, 1H), 1.31 (t, J=7.5 Hz, 3H), 1.56-1.70 (m, 2H), 1.88-1.98(m, 2H), 2.12 (s, 6H), 2.86 (q, J=7.5 Hz, 2H), 3.10 (d, J=6.8 Hz, 2H),3.33-3.44 (m, 1H), 3.50 (dt, J=2.0, 12.0 Hz, 2H), 3.95 (s, 3H),4.04-4.12 (m, 2H), 6.56 (dd, J=1.4, 6.7 Hz, 1H), 6.82 (s, 2H), 7.13 (dd,J=6.8, 8.8 Hz, 1H), 7.53 (dd, J=1.4, 8.8 Hz, 1H).

[0456] MS(ESI) m/z 434 MH⁺

Example 49

[0457]N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylamine

[0458] (Yellow Oil)

[0459]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.30-0.40 (m, 2H),0.75-0.88 (m, 1H), 1.29 (t, J=7.5 Hz, 3H), 1.51-1.64 (m, 2H), 1.83-1.92(m, 2H), 2.83 (q, J=7.5 Hz, 2H), 3.05 (d, J=6.6 Hz, 2H), 3.26-3.38 (m,1H), 3.44 (dt, J=2.0, 12.0 Hz, 2H), 3.77 (s, 6H), 3.98-4.06 (m, 2H),6.64 (dd, J=1.4, 6.9 Hz, 1H), 6.76 (s, 2H), 7.08 (dd, J=6.9, 8.8 Hz,1H), 7.48 (dd, J=1.4, 8.8 Hz, 1H).

[0460] MS(ESI) m/z 470 MH⁺

Example 50

[0461]N-[2-Ethyl-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

[0462] (White Crystals)

[0463]¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7.4 Hz, 3H), 1.19 (t, J=7.5Hz, 3H), 1.25-1.38 (m, 2H), 1.46-1.60 (m, 2H), 1.74-1.83 (m, 2H), 2.01(s, 6H), 2.72 (q, J=7.4 Hz, 2H), 3.08 (t, J=7.2 Hz, 2H), 3.11-3.22 (m,1H), 3.37 (dt, J=2.0, 12.0 Hz, 2H), 3.84 (s, 3H), 3.92-4.00 (m, 2H),6.45 (dd, J=1.4, 6.6 Hz, 1H), 6.70 (s, 2H), 7.02 (dd, J=6.8, 8.8 Hz,1H), 7.41 (dd, J=1.4, 8.9 Hz, 1H).

[0464] MS(ESI) m/z 422 MH⁺

Example 51

[0465]N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

[0466] (Yellow Crystals)

[0467]¹H NMR (400 MHz, CDCl₃) δ 0.84 (t, J=7.3 Hz, 3H), 1.20 (t, J=7.5Hz, 3H), 1.23-1.37 (m, 2H), 1.46-1.60 (m, 2H), 1.74-1.84 (m, 2H), 2.73(q, J=7.5 Hz, 2H), 3.07 (t, J=7.3 Hz, 2H), 3.10-3.21 (m, 1H), 3.36 (dt,J=1.8, 12.0 Hz, 2H), 3.70 (s, 6H), 3.90-3.99 (m, 2H), 6.57 (dd, J=1.4,6.9 Hz, 1H), 6.69 (s, 2H), 7.01 (dd, J=6.9, 8.9 Hz, 1H), 7.40 (dd,J=1.4, 8.9 Hz, 1H)

[0468] MS(ESI) m/z 458 MH⁺

Example 52

[0469]N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0470] (Yellow Oil)

[0471]¹H NMR (400 MHz, CDCl₃) δ −0.10-−0.04 (m, 2H), 0.24-0.32 (m, 2H),0.70-0.80 (m, 1H), 1.21 (t, J=7.6 Hz, 3H), 1.46-1.60 (m, 2H), 1.76-1.84(m, 2H), 1.97 (s, 3H), 2.40 (s, 3H), 2.70-2.80 (m, 2H), 2.98 (d, J=6.4Hz, 2H), 3.22-3.30 (m, 1H), 3.34-3.42 (m, 2H), 3.68 (s, 3H), 3.92-3.99(m, 2H), 6.51 (dd, J=1.2, 6.8 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 7.02(dd, J=6.8, 9.2 Hz, 1H), 7.40 (dd, J=1.2, 9.2 Hz, 1H).

Example 53

[0472]N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-tetrahydro-2H-4-pyranylamine

[0473] (Yellow Oil)

[0474]¹H NMR (400 MHz, CDCl₃) δ 1.19 (t, J=7.2 Hz, 3H), 1.48-1.60 (m,2H), 1.60-1.74 (m, 2H), 1.76-1.84 (m, 2H), 1.97 (s, 3H), 2.40 (s, 3H),2.68-2.76 (m, 2H), 3.12-3.20 (m, 1H), 3.29 (t, J=6.4 Hz, 2H), 3.36 (dt,J=1.6, 11.6 Hz, 2H), 3.69 (s, 3H), 3.94-4.00 (m, 2H), 4.51 (td, J=5.6,47.6 Hz, 2H), 6.54 (dd, J=1.2, 6.8 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H),7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.39 (dd, J=1.2, 8.8 Hz, 1H).

Example 54

[0475][2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)-N-tetrahydro-2H-4-pyranylamine

[0476] (Yellow Oil)

[0477]¹H NMR (400 MHz, CDCl₃) δ 1.20 (t, J=7.6 Hz, 3H), 1.47-1.58 (m,2H), 1.77-1.84 (m, 2H), 1.98 (s, 3H), 2.40 (s, 3H), 2.68-2.76 (m, 2H),3.16-3.25 (m, 1H), 3.26 (s, 3H), 3.27-3.40 (m, 6H), 3.69 (s, 3H),3.92-3.99 (m, 2H), 6.53 (dd, J=1.2, 6.8 Hz, 1H), 6.70 (s, 1H), 6.77 (s,1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.40 (dd, J=1.2, 8.8 Hz, 1H).

Example 55

[0478]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0479] (Yellow Oil)

[0480]¹H NMR (400 MHz, CDCl₃) δ −0.06-−0.01 (m, 2H), 0.26-0.32 (m, 2H),0.70-0.80 (m, 1H), 1.22 (t, J=7.6 Hz, 3H), 1.46-1.62 (m, 2H), 1.76-1.84(m, 2H), 2.43 (s, 3H), 2.75 (q, J=7.6 Hz, 2H), 2.97 (d, J=6.8 Hz, 2H),3.22-3.30 (m, 1H), 3.32-3.40 (m, 2H), 3.69 (s, 6H), 3.92-3.98 (m, 2H),6.51 (s, 2H), 6.58 (dd, J=1.6, 6.8 Hz, 1H), 7.01 (dd, J=6.8, 8.8 Hz,1H), 7.39 (dd, J=1.6, 8.8 Hz, 1H).

Example 56

[0481]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-tetrahydro-2H-4-pyranylamine

[0482] (Yellow Oil)

[0483]¹H NMR (400 MHz, CDCl₃) δ 1.20 (t, J=7.2 Hz, 3H), 1.49-1.60 (m,2H), 1.61-1.74 (m, 2H), 1.77-1.84 (m, 2H), 2.43 (s, 3H), 2.72 (q, J=7.2Hz, 2H), 3.12-3.20 (m, 1H), 3.28 (t, J=6.8 Hz, 2H), 3.36 (dt, J=2.0,12.4 Hz, 2H), 3.70 (s, 6H), 3.93-3.99 (m, 2H), 4.50 (td, J=6.0, 47.2 Hz,2H), 6.51 (s, 2H), 6.62 (dd, J=1.2, 6.8 Hz, 1H), 7.04 (dd, J=6.8, 8.8Hz, 1H), 7.38 (dd, J=1.2, 8.8 Hz, 1H).

Example 57

[0484]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)-N-tetrahydro-2H-4-pyranylamine

[0485] (Yellow Oil)

[0486]¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J=7.6 Hz, 3H), 1.47-1.59 (m,2H), 1.77-1.84 (m, 2H), 2.43 (s, 3H), 2.72 (q, J=7.6 Hz, 2H), 3.15-3.24(m, 1H), 3.26 (s, 3H), 3.27-3.40 (m, 6H), 3.70 (s, 3H), 3.92-3.98 (m,2H), 6.51 (s, 2H), 6.61 (dd, J=1.6, 6.8 Hz, 1H), 7.04 (dd, J=6.8, 8.8Hz, 1H), 7.38 (dd, J=1.6, 8.8 Hz, 1H)

Example 58

[0487]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0488] (Yellow Oil)

[0489]¹H NMR (400 MHz, CDCl₃) δ −0.10-−0.01 (m, 2H), 0.23-0.32 (m, 2H),0.70-0.80 (m, 1H), 1.22 (t, J=7.6 Hz, 3H), 1.46-1.58 (m, 2H), 1.77-1.85(m, 2H), 2.00 (s, 3H), 2.68-2.82 (m, 2H), 2.98 (d, J=7.6 Hz, 2H),3.22-3.31 (m, 1H), 3.38 (dt, J=2.0, 12.0 Hz, 2H), 3.68 (s, 3H), 3.86 (s,3H), 3.73-4.00 (m, 2H), 6.44 (d, J=2.0 Hz, 1H), 6.48 (d, J=2.0 Hz, 1H),6.51 (dd, J=1.2, 6.8 Hz, 1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.40 (dd,J=1.2, 8.8 Hz, 1H).

Example 59

[0490]N-[7-(2,4-Dimethoxy-6-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-tetrahydro-2H-4-pyranylamine

[0491] (Yellow Oil)

[0492]¹H NMR (400 MHz, CDCl₃) δ 1.20 (t, J=7.6 Hz, 3H), 1.48-1.60 (m,2H), 1.60-1.74 (m, 2H), 1.76-1.84 (m, 2H), 2.00 (s, 3H), 2.72 (q, J=7.6Hz, 2H), 3.12-3.20 (m, 1H), 3.29 (t, J=6.8 Hz, 2H), 3.36 (dt, J=2.0,12.0 Hz, 2H), 3.68 (s, 3H), 3.86 (s, 3H), 3.93-4.00 (m, 2H), 4.51 (td,J=6.0, 47.2 Hz, 2H), 6.44 (d, J=2.0 Hz, 1H), 6.48 (d, J=2.0 Hz, 1H),6.54 (dd, J=1.6, 6.8 Hz, 1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.38 (dd,J=1.6, 8.8 Hz, 1H).

Example 60

[0493]N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

[0494] (Yellow Oil)

[0495]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.32-0.42 (m, 2H),0.78-0.88 (m, 1H), 1.30 (t, J=7.6 Hz, 3H), 1.30-1.44 (m, 1H), 1.66-1.76(m, 2H), 2.06 (s, 3H), 2.06-2.18 (m, 1H), 2.49 (s, 3H), 2.83(q, J=7.6Hz, 2H), 3.06 (d, J=6.8 Hz, 2H), 3.18-3.38 (m, 3H), 3.77 (s, 3H),3.86-3.96 (m, 1H), 4.12-4.20 (m, 1H), 6.61 (dd, J=1.2, 6.8 Hz, 1H), 6.78(s, 1H), 6.86 (s, 1H), 7.12 (dd, J=6.8, 8.8 Hz, 1H), 7.48 (dd, J=1.2,8.8 Hz, 1H).

Example 61

[0496]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[0497] (Yellow Oil)

[0498]¹H NMR (400 MHz, CDCl₃) δ −0.01-0.03 (m, 2H), 0.34-0.40 (m, 2H),0.80-0.90 (m, 1H), 1.23 (t, J=7.6 Hz, 3H), 1.20-1.34 (m, 2H), 1.56-1.62(m, 1H), 1.74-1.80 (m, 2H), 2.45 (s, 3H), 2.77 (q, J=7.6 Hz, 2H), 2.89(d, J=6.4 Hz, 2H), 3.06 (d, J=6.8 Hz, 2H), 3.32 (dt, J=2.0, 11.6 Hz,2H), 3.71 (s, 6H), 3.92-3.98 (m, 2H), 6.53 (s, 2H), 6.60 (dd, J=1.2, 6.8Hz, 1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.45 (dd, J=1.2, 8.8 Hz, 1H)

Example 62

[0499]N,N-Dicyclopropylmethyl-N-[2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0500]2-Ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitropyrazolo[1,5-a]pyridine(185 mg) was dissolved in a mixture of ethanol (7 mL) and water (7.5mL), and then acetic acid (0.3 mL) and zinc powder (185 mg) were addedand the reaction mixture was heated at 60° C. for 20 minutes. Thereaction mixture was filtered with celite, and the obtained filtrate wasconcentrated under reduced pressure. Water was added, extraction wasperformed with ethyl acetate, the extract was washed with saturatedaqueous sodium hydrogencarbonate and brine and dried over magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-amineas a crude product.

[0501] To a solution of the obtained crude2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-aminein tetrahydrofuran (10 mL) there were added cyclopropanecarboxyaldehyde(0.20 mL) and 3 M sulfuric acid (0.87 mL), and then sodium borohydride(79 mg) was slowly added at 0° C. and the mixture was stirred at roomtemperature for 30 minutes. A 5 N aqueous sodium hydroxide solution wasadded while cooling on ice to make the reaction mixture basic, and thenextraction was performed with ethyl acetate, the extract was washed withsaturated aqueous sodium hydrogencarbonate and brine and dried overmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was subjected to silica gel column chromatography(20 g), and the title compound (185 mg) was obtained from then-hexane:ethyl acetate (6:1) fraction as white crystals.

[0502]¹H NMR (400 MHz, CDCl₃) δ −0.32-0.46 (m, 8H), 0.70-0.88 (m, 2H),1.20 (t, J=7.5 Hz, 3H), 1.97 (s, 3H), 2.38 (s, 3H), 2.74-2.97 (m, 6H),3.67 (s, 3H), 3.93 (s, 3H), 6.34 (d, J=7.7 Hz, 1H), 6.38 (d, J=7.7 Hz,1H), 6.68 (s, 1H), 6.75 (s, 1H).

[0503] MS(ESI) m/z 434 MH⁺

Example 63

[0504]N-[2-Ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1-ethylpropyl)amine

[0505] To a solution of2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-amine(100 mg) in acetic acid (10 mL) there was added 3-pentanone (0.04 mL),and then sodium triacetoxyborohydride (85.0 mg) was slowly added at roomtemperature and the mixture was stirred for 3 hours. A 5 N aqueoussodium hydroxide solution was added while cooling on ice, and thenextraction was performed with ethyl acetate, the organic layer waswashed with saturated aqueous sodium hydrogencarbonate and brine anddried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The obtained residue was subjected to silica gelcolumn chromatography (10 g), and the title compound (69 mg) wasobtained from the n-hexane:ethyl acetate (5:1) fraction as yellowcrystals.

[0506]¹H NMR (400 MHz, CDCl₃) δ 0.94 (t, J=7.5 Hz, 3H), 0.96 (t, J=7.5Hz, 3H), 1.21 (t, J=7.5 Hz, 3H), 1.42-1.55 (m, 4H), 1.98 (s, 3H), 2.38(s, 3H), 2.70 (q, J=7.5 Hz, 2H), 2.87-2.96 (m, 1H), 3.67 (s, 3H), 3.92(s, 3H), 6.20 (d, J=7.7 Hz, 1H), 6.28 (d, J=7.5 Hz, 1H), 6.67 (s, 1H),6.74 (s, 1H)

[0507] MS(ESI) m/z 396 MH⁺

Example 64

[0508] tert-ButylN-[7-(2,4-dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate

[0509] After dissolving tert-butylN-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (220 mg) intetrahydrofuran (3 mL), a solution of n-butyllithium in hexane (1.6 M;1.51 mL) was added dropwise at −78° C. under a nitrogen stream, and themixture was stirred for 30 minutes. A solution of1,2-dibromo-1,1,2,2-tetrachloroethane (384 mg) in tetrahydrofuran (2 mL)was added to the reaction mixture, and stirring was continued for 30minutes. Saturated aqueous ammonium chloride was added to the reactionmixture, the temperature was raised to room temperature, extraction wasperformed with ethyl acetate and the extract was washed with water andbrine. After drying over anhydrous magnesium sulfate and filtration, thesolvent was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography, and tert-butylN-[7-bromo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate wasobtained from the n-hexane:ethyl acetate (10:1) fraction as yellowcrystals. After dissolving this in 1,2-dimethoxyethane (6 mL) and water(1 mL), 2,4-dichlorophenylboric acid (191 mg),tetrakis(triphenylphosphine)palladium (0) complex (116 mg) and bariumhydroxide octahydrate (315 mg) were added and the mixture was heated andstirred at 80° C. for 4 hours under a nitrogen stream. Water was addedto the reaction mixture, extraction was performed with ethyl acetate andthe extract was washed with brine. After drying over anhydrous magnesiumsulfate and filtration, the solvent was concentrated under reducedpressure, the residue was purified by silica gel column chromatography,and the title compound (160 mg) was obtained from the n-hexane:ethylacetate (20:1) fraction as a yellow oil.

[0510]¹H NMR (400 MHz, CDCl₃) δ 1.58 (s, 9H), 2.46 (s, 3H), 6.67 (m,1H), 7.16 (dd, J=6.8, 8.8 Hz, 1H), 7.36 (dd, J=2.0, 8.4 Hz, 1H), 7.43(d, J=8.4 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H).

Example 65

[0511] tert-ButylN-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate

[0512] After dissolving tert-butylN-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (2.0g) in 1,2-dimethoxyethane (60 mL) and water (30 mL),4,6-dimethyl-2-methoxyphenylboric acid (1.33 g),tetrakis(triphenylphosphine)palladium (0) complex (865 mg) and bariumhydroxide octahydrate (2.34 g) were added and the mixture was heated andstirred at 80° C. for 3 hours. Water was added to the reaction mixture,extraction was performed with ethyl acetate and the extract was washedwith brine. After drying over anhydrous magnesium sulfate andfiltration, the solvent was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography, and the titlecompound (2.1 g) was obtained from the n-hexane:ethyl acetate (20:1)fraction as yellow amorphous.

[0513]¹H NMR (400 MHz, CDCl₃) δ 1.54 (br s, 9H), 1.98 (s, 3H), 2.39 (s,3H), 2.42 (s, 3H), 3.64 (s, 3H), 6.02-6.12 (m, 1H), 6.58 (dd, J=1.6, 6.8Hz, 1H), 7.13 (dd, J=6.8, 9.2 Hz, 1H), 7.42-7.48 (m, 1H).

Example 66

[0514]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0515] After dissolving tert-butylN-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate(400 mg) in N,N-dimethylformamide (5 mL), sodium hydride (60%, 58 mg)was added while cooling on ice, and then (bromomethyl)cyclopropane (111μL) was added and the mixture was stirred for 1 hour at 40° C. Water wasadded to the reaction mixture, extraction was performed with ethylacetate and the extract was washed with brine. After drying the obtainedorganic layer over anhydrous magnesium sulfate and filtering it, thesolvent was concentrated under reduced pressure to obtain crudetert-butylN-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate.This was dissolved in ethyl acetate (10 mL) without purification, a 4 Nhydrochloric acid/ethyl acetate solution (20 mL) was added, and themixture was stirred at 40° C. for 1 hour. The reaction mixture wasneutralized with 5 N aqueous sodium hydroxide while cooling on ice, andthen extraction was performed with ethyl acetate and the organic layerwas washed with brine. After drying over anhydrous magnesium sulfate andfiltration, the solvent was distilled off under reduced pressure toobtain the title compound (368 mg) as a yellow oil.

[0516]¹H NMR (400 MHz, CDCl₃) δ 0.18-0.23 (m, 2H), 1.50-0.55 (m, 1H),1.1.04-1.13 (m, 1H), 1.98 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 2.99 (d,J=6.8 Hz, 2H), 3.66 (s, 3H), 6.51 (dd, J=1.2, 6.8 Hz, 1H), 6.66 (br s,1H), 6.74 (br s, 1H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.42 (dd, J=1.6, 8.8Hz, 1H)

Example 67

[0517]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0518] tert-ButylN-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate(50 mg) was dissolved in a 4 N hydrochloric acid/ethyl acetate solution(2 mL), and the mixture was stirred at room temperature for 1 hour. Thereaction mixture was neutralized with 5 N aqueous sodium hydroxide andextracted with ethyl acetate, and the organic layer was concentrated toobtain7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridine-3-amine.This was dissolved in tetrahydrofuran (1 mL), and after addingpropionaldehyde (0.078 mL) and 3 M aqueous sulfuric acid (0.363 mL),sodium borohydride (27 mg) was added in five portions at a time whilevigorously stirring on ice, and stirring was continued for 30 minutes.After adding saturated aqueous sodium hydrogencarbonate to neutralizethe reaction mixture, extraction was performed with ethyl acetate andthe organic layer was concentrated. The residue was purified by silicagel column chromatography, and the title compound (20.6 mg) was obtainedfrom the n-hexane:ethyl acetate (7:1) fraction as a light yellow oil.

[0519]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.6 Hz, 6H), 1.34-1.44 (m,4H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 3.01-3.06 (m, 4H), 3.63(s, 3H), 6.49 (dd, J=1.2, 6.8 Hz, 1H), 6.67 (s, 1H). 6.75 (s, 1H), 7.03(dd, J=6.8, 8.8 Hz, 1H), 7.39 (dd, J=1.2, 8.8 Hz, 1H)

[0520] The compounds of Examples 68 to 101 were synthesized according tothe production method of Example 67.

Example 68

[0521]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0522] (Light Yellow Oil)

[0523]¹H NMR (400 MHz, CDCl₃) δ 0.84-0.92 (m, 6H), 1.34-1.44 (m, 4H),2.40-2.48 (m, 6H), 3.00-3.10 (m, 4H), 3.70 (s, 6H), 6.49 (s, 2H),6.56-6.60 (m, 1H), 6.99-7.05 (m, 1H), 7.35-7.42 (m, 1H).

Example 69

[0524]N-[7-(2,6-Dimethoxy-3-pyridyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0525] (Light Yellow Oil)

[0526]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=6.8 Hz, 6H), 1.33-1.42 (m,4H), 2.50 (s, 3H), 2.95-3.06 (m, 4H), 3.93 (s, 3H), 3.99 (s, 3H), 6.42(d, J=8.4 Hz, 1H), 6.67-6.74 (m, 1H), 6.98-7.06 (m, 1H), 7.34-7.42 (m,1H), 7.98 (d, J=8.4 Hz, 1H).

Example 70

[0527]N-[7-(6-Methoxy-2-methyl-3-pyridyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0528] (Light Yellow Oil)

[0529]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.2 Hz, 6H), 1.32-1.42 (m,4H), 2.30 (s, 3H), 2.47 (s, 3H), 3.00-3.06 (m, 4H), 4.00 (s, 3H), 6.48(d, J=6.8 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 7.03 (dd, J=6.8, 8.4 Hz, 1H),7.42 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H)

Example 71

[0530]N3,N3-Dipropyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

[0531] (Light Yellow Oil)

[0532]¹H NMR (400 MHz, CDCl₃) δ 0.82 (t, J=7.6 Hz, 6H), 1.19-1.70 (m,4H), 2.06 (s, 3H), 2.42 (s, 3H), 2.90-3.00 (m, 4H), 3.13 (s, 6H),6.40-6.47 (m, 2H), 6.92-7.02 (m, 1H), 7.30-7.40 (m, 1H), 8.08 (s, 1H).

[0533] MS(ESI) m/z 398 MH⁺

Example 72

[0534]N,N-Dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0535] (Light Yellow Oil)

[0536]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.04 (m, 4H), 0.28-0.34 (m, 4H),0.80-0.90 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.97-3.04(m, 4H), 3.68 (s, 3H), 6.49 (dd, J=1.2, 6.8 Hz, 1H), 6.67 (s, 1H). 6.76(s, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.46 (dd, J=1.2, 8.8 Hz, 1H).

Example 73

[0537]N,N-Diisobutyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0538] (Light Yellow Oil)

[0539] MS(ESI) m/z 426 MH⁺

Example 74

[0540]N-[7-(2,4-Dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0541] (Light Yellow Oil)

[0542]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.2 Hz, 6H), 1.35-1.44 (m,4H), 2.02 (s, 3H), 2.43 (s, 3H), 3.03 (t, J=7.6 Hz, 4H), 3.67 (s, 3H),3.86 (s, 3H), 6.42 (br s, 1H), 6.46 (br s, 1H), 6.47-6.51 (m, 1H),7.00-7.05 (m, 1H), 7.37-7.40 (m, 1H).

Example 75

[0543]N-[7-(2-Methoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0544] (Light Yellow Oil)

[0545]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.6 Hz, 6H), 1.35-1.44 (m,4H), 2.44 (s, 3H), 2.47 (s, 3H), 3.03 (t, J=7.6 Hz, 4H), 3.77 (s, 3H),6.61 (dd, J=1.2, 6.8 Hz, 1H), 6.84 (s, 1H), 7.02 (dd, J=6.8, 8.8 Hz,1H), 7.37-7.40 (m, 1H), 7.43 (d, J=7.6 Hz, 1H)

Example 76

[0546]N,N-Dicyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0547] (Colorless Oil)

[0548]¹H NMR (400 MHz, CDCl₃) δ −0.01-0.05 (m, 4H), 0.28-0.34 (m, 4H),0.80-0.92 (m, 2H), 2.43 (m, 3H), 2.46 (s, 3H), 3.00 (d, J=6.4 Hz, 2H),3.69 (s. 6H), 6.49 (s, 2H), 6.57 (dd, J=1.6, 6.8 Hz, 1H), 7.02 (dd,J=6.8, 8.8 Hz, 1H), 7.44 (dd, J=1.6, 8.8 Hz, 1H).

Example 77

[0549]N-[7-(4-Chloro-2-methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[0550] (Light Yellow Oil)

[0551]¹H NMR (400 MHz, CDCl₃) δ 0.02-0.06 (m, 4H), 0.30-0.34 (m, 4H),0.80-0.90 (m, 2H), 2.48 (s, 3H), 2.99 (d, J=6.4 Hz, 4H), 3.76 (s, 3H),6.59 (dd, J=1.6, 6.8 Hz, 1H), 7.00-7.03 (m,21H), 7.06 (dd, J=2.0, 8.0Hz, 1H), 7.46-7.50 (m, 2H)

Example 78

[0552]N-[7-(2-Chloro-4-methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[0553] (Light Yellow Oil)

[0554]¹H NMR (400 MHz, CDCl₃) δ 0.01-0.06 (m, 4H), 0.28-0.35 (m, 4H),0.80-0.90 (m, 2H), 2.49 (s, 3H), 2.99 (d, J=6.4 Hz, 4H), 3.88 (s, 3H),6.55-6.58 (m, 1H), 6.90-6.94 (m, 1H), 7.01-7.07 (m, 2H), 7.45-7.53 (m,2H).

Example 79

[0555]N,N-Dicyclopropylmethyl-N-[7-(4-methoxy-2-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0556] (Light Yellow Oil)

[0557]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.04 (m, 4H), 0.28-0.34 (m, 4H),0.78-0.88 (m, 2H), 2.10 (s, 3H), 2.48 (s, 3H), 2.99 (d, J=6.8 Hz, 4H),3.87 (s, 3H), 6.47-6.51 (m, 1H), 6.81-6.86 (m, 1H), 7.03 (dd, J=6.8, 8.8Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.45-7.49 (m, 1H).

Example 80

[0558]N-[7-(4-Methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0559] (Light Yellow Crystals)

[0560]¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=7.3 Hz, 6H), 1.30-1.46 (m,4H), 2.01 (s, 6H), 2.41 (s, 3H), 3.03 (t, J=7.1 Hz, 4H), 3.84 (s, 3H),6.43 (br d, J=6.4 Hz, 1H), 6.69 (s, 2H), 6.98-7.07 (m, 1H), 7.40 (br d,J=9.3 Hz, 1H).

[0561] MS(ESI) m/z 398 MH⁺

Example 81

[0562]N,N-Dicyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0563] (Light Yellow Crystals)

[0564]¹H NMR (400 MHz, CDCl₃) δ −0.06-0.10 (m, 4H), 0.22-0.36 (m, 4H),0.80-0.94 (m, 2H), 2.01 (s, 6H), 2.44 (s, 3H), 3.01 (d, J=6.4 Hz, 4H),3.85 (s, 3H), 6.44 (br d, J=6.4 Hz, 1H), 6.70 (s, 2H), 7.00-7.09 (m,1H), 7.47 (br d, J=8.6 Hz, 1H).

[0565] MS(ESI) m/z 422 MH⁺

Example 82

[0566]N,N-Dicyclopropylmethyl-N-[7-[4-methoxy-2-(trifluoromethyl)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0567] (Yellow Oil)

[0568]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.04 (m, 4H), 0.27-0.32 (m, 4H),0.80-0.90 (m, 2H), 2.42 (s, 3H), 2.95-3.05 (m, 4H), 3.93 (s, 3H), 6.50(dd, J=1.6, 6.8 Hz, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.15 (dd, J=2.4,8.4 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.49 (dd,J=1.6, 8.8 Hz, 1H).

Example 83

[0569]N-[7-[2-Chloro-4-(trifluoromethoxy)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[0570] (Yellow Oil)

[0571]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.04 (m, 4H), 0.28-0.34 (m, 4H),0.80-0.90 (m, 2H), 2.48 (s, 3H), 3.00 (d, J=6.4 Hz, 4H), 6.58 (dd,J=1.6, 6.8 Hz, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.23-7.27 (m, 1H),7.40-7.42 (m, 1H), 7.54 (dd, J=1.6, 8.8 Hz, 1H), 7.59 (dd, J=8.4 Hz,1H).

Example 84

[0572]N,N-Dicyclopropylmethyl-N-[7-(4-methyl-1,3-benzodioxol-5-yl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0573] (Yellow Crystals)

[0574]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.04 (m, 4H), 0.28-0.33 (m, 4H),0.80-0.90 (m, 2H), 1.95 (s, 3H), 2.50 (s, 3H), 3.00 (d, J=6.8 Hz, 4H),6.04 (s, 2H), 6.50 (dd, J=1.2, 6.8 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.93(d, J=8.4 Hz, 1H), 7.48 (dd, J=1.2, 8.8 Hz, 1H).

Example 85

[0575]N-[7-(2,4-Dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0576] (Yellow Oil)

[0577]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.3 Hz, 6H), 1.30-1.45 (m,4H), 2.48 (s, 3H), 3.02 (t, J=7.3 Hz, 4H), 3.76 (s, 3H), 3.88 (s, 3H),6.56-6.64 (m, 3H), 7.01 (dd, J=6.9, 8.9 Hz, 1H), 7.37 (dd, J=1.4, 8.8Hz, 1H), 7.49 (d, J=8.9 Hz, 1H).

Example 86

[0578]N,N-Dicyclopropylmethyl-N-(7-(2,4-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0579] (Yellow Oil)

[0580]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.08 (m, 4H), 0.25-0.34 (m, 4H),0.75-0.88 (m, 2H), 2.47 (s, 3H), 2.97 (d, J=6.8 Hz, 4H), 3.72 (s, 3H),3.86 (s, 3H), 6.54-6.60 (m, 3H), 6.99 (dd, J=6.8, 8.8 Hz, 1H), 7.41 (dd,J=1.4, 8.8 Hz, 1H), 7.47 (dd, J=0.8, 8.0 Hz, 1H).

Example 87

[0581]N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0582] (Yellow Crystals)

[0583]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.3 Hz, 6H), 1.33-1.45 (m,4H), 2.43 (s, 3H), 3.02 (t, J=7.3 Hz, 4H), 3.70 (s, 6H), 6.54 (dd,J=1.4, 6.9 Hz, 1H), 6.67 (s, 2H), 7.02 (dd, J=6.9, 8.9 Hz, 1H), 7.40(dd, J=1.5, 8.8 Hz, 1H).

[0584] MS(ESI) m/z 434 MH⁺

Example 88

[0585]N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[0586] (Yellow Crystals)

[0587]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 4H), 0.26-0.34 (m, 4H),0.77-0.91 (m, 2H), 2.45 (s, 3H), 2.99 (d, J=6.6 Hz, 4H), 3.69 (s, 6H),6.54 (dd, J=1.5, 6.8 Hz, 1H), 6.66 (s, 2H), 7.02 (dd, J=6.8, 8.8 Hz,1H), 7.45 (dd, J=1.4, 8.9 Hz, 1H)

[0588] MS(ESI) m/z 458 MH⁺

Example 89

[0589]N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0590] (Yellow Crystals)

[0591]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.4 Hz, 6H), 1.33-1.45 (m,4H), 2.41 (s, 3H), 2.43 (s, 3H), 3.03 (t, J=7.4 Hz, 4H), 3.70 (s, 3H),6.55 (dd, J=1.3, 6.8 Hz, 1H), 6.72 (s, 1H), 6.95 (s, 1H), 7.04 (dd,J=6.9, 8.9 Hz, 1H), 7.43 (dd, J=1.4, 8.9 Hz, 1H).

[0592] MS(ESI) m/z 418 MH⁺

Example 90

[0593]N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[0594] (Yellow Crystals)

[0595]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.08 (m, 4H), 0.26-0.36 (m, 4H),0.78-0.92 (m, 2H), 2.41 (s, 3H), 2.45 (s, 3H), 3.00 (d, J=6.6 Hz, 4H),3.69 (s, 3H), 6.55 (dd, J=1.5, 6.8 Hz, 1H), 6.73 (s, 1H), 6.96 (s, 1H),7.04 (dd, J=6.8, 9.0 Hz, 1H), 7.49 (dd, J=1.4, 8.9 Hz, 1H)

[0596] MS(ESI) m/z 442 MH⁺

Example 91

[0597]N,N-Dicyclopropylmethyl-N-[2-(methylsulfanyl)-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0598] (Light Yellow Crystals)

[0599]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.06 (m, 4H), 0.28-0.34 (m, 4H),0.80-0.90 (m, 2H), 2.46 (s, 3H), 2.99 (d, J=6.4 Hz, 4H), 3.69 (s, 6H),3.89 (s, 3H), 6.23 (s, 2H), 6.56 (dd, J=1.2, 6.8 Hz, 1H), 7.02 (dd,J=6.8, 8.8 Hz, 1H), 7.43 (dd, J=1.2, 8.8 Hz, 1H).

Example 92

[0600]N,N-Dicyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0601] (Yellow Oil)

[0602]¹H NMR (400 MHz, CDCl₃) δ −0.01-0.04 (m, 4H), 0.28-0.34 (m, 4H),0.80-0.92 (m, 2H), 2.02 (m, 3H), 2.45 (s, 3H), 2.96-3.04 (m, 4H), 3.67(s, 3H), 3.87 (s. 6H), 6.42 (d, J=2.0 Hz, 2H), 6.47 (d, J=2.0 Hz, 2H),6.49 (dd, J=1.6, 6.8 Hz, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.46 (dd,J=1.6, 8.8 Hz, 1H).

Example 93

[0603]N3,N3-Dicyclopropylmethyl-7-[6-(dimethylamino)-2-methyl-3-pyridyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

[0604] (Yellow Oil)

[0605]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.40 (m, 4H), 0.29-0.33 (m, 4H),0.80-0.90 (m, 2H), 2.23 (s, 3H), 2.51 (s, 3H), 2.99 (d, J=6.8 Hz, 4H),3.15 (s, 6H), 6.42-6.48 (m, 2H), 7.00-7.04 (m, 1H), 7.44 (dd, J=1.6, 8.8Hz, 1H), 7.52 (d, J=8.8 Hz, 1H)

Example 94

[0606]N3,N3-Dicyclopropylmethyl-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

[0607] (Yellow Oil)

[0608]¹H NMR (400 MHz, CDCl₃) δ −0.01-0.02 (m, 4H), 0.26-0.32 (m, 4H),0.80-0.90 (m, 2H), 1.95 (s, 3H), 2.15 (s, 3H), 2.45 (s, 3H), 3.00 (d,J=6.8 Hz, 4H), 3.13 (s, 6H), 6.30 (s, 1H), 6.43 (dd, J=1.6, 6.8 Hz, 1H),7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.46 (dd, J=1.6, 8.8 Hz, 1H).

Example 95

[0609]N3,N3-Dicyclopropylmethyl-7-[6-(dimethylamino)-3-pyridyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

[0610] (Yellow Oil)

[0611]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.70 (m, 4H), 0.29-0.34 (m, 4H),0.80-0.85 (m, 2H), 2.61 (s, 3H), 2.95 (d, J=6.8 Hz, 4H), 3.17 (s, 6H),6.60-6.64 (m, 2H), 7.01-7.05 (m, 1H), 7.39-7.42 (m, 1H), 8.28-8.31 (m,1H), 8.71-8.72 (m, 1H).

Example 96

[0612]N,N-Dicyclopropylmethyl-N-[7-(4-methoxy-6-methyl-3-pyridyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0613] (Yellow Oil)

[0614]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.08 (m, 4H), 0.26-0.37 (m, 4H),0.74-0.93 (m, 2H), 2.46 (s, 3H), 2.79 (s, 3H), 2.97 (d, J=6.8 Hz, 4H),3.88 (s, 3H), 6.60 (dd, J=1.3, 6.8 Hz, 1H), 6.90 (s, 1H), 7.02 (dd,J=6.8, 8.9 Hz, 1H), 7.53 (dd, J=1.4, 8.9 Hz, 1H), 8.80 (s, 1H).

Example 97

[0615]N,N-Dicyclopropylmethyl-N-[7-(4,6-dimethyl-3-pyridyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0616] (Brown Oil)

[0617]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.08 (m, 4H), 0.24-0.36 (m, 4H),0.76-0.98 (m, 2H), 2.11 (s, 3H), 2.46 (s, 3H), 2.60 (s, 3H), 2.98 (d,J=6.8 Hz, 4H), 6.52 (dd, J=1.3, 6.8 Hz, 1H), 7.05 (dd, J=6.8, 8.8 Hz,1H), 7.12 (s, 1H), 7.52 (dd, J=1.5, 8.9 Hz, 1H), 8.46 (s, 1H).

Example 98

[0618]N3,N3-Dicyclopropylmethyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

[0619] (Light Yellow Oil)

[0620]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.08 (m, 4H), 0.26-0.36 (m, 4H),0.78-0.90 (m, 2H), 2.09 (s, 3H), 2.50 (s, 3H), 2.99 (d, J=6.5 Hz, 4H),3.15 (s, 6H), 6.45 (s, 1H), 6.50 (dd, J=1.6, 6.8 Hz, 1H), 7.03 (dd,J=6.8, 8.8 Hz, 1H), 7.47 (dd, J=1.6, 8.9 Hz, 1H), 8.15 (s, 1H)

Example 99

[0621]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-ditetrahydro-3-furanylmethylamine

[0622] (Yellow Oil)

[0623]¹H NMR (400 MHz, CDCl₃) δ 1.55-1.66 (m, 2H), 1.89-1.98 (m, 2H),1.98-2.01 (m, 3H), 2.18-2.28 (m, 2H), 2.40 (s, 3H), 2.43 (s, 3H),2.96-3.03 (m, 2H), 3.11-3.19 (m, 2H), 3.56-3.61 (m, 2H), 3.64-3.70 (m,5H), 3.74-3.84 (m, 4H), 6.53 (d, J=1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76(s, 1H), 7.08 (dd, J=6.8, 8.8 Hz, 1H), 7.31 (dd, J=1.6, 8.8 Hz, 1H).

Example 100

[0624]N,N-Di(3-furylmethyl)-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0625] (Yellow Oil)

[0626]¹H NMR (400 MHz, CDCl₃) δ 1.97 (s, 6H), 2.42 (s, 3H), 3.84 (s,3H), 4.12 (s, 4H), 6.28-6.33 (m, 2H), 6.39 (dd, J=1.3, 8.1 Hz, 1H), 6.68(s, 2H), 6.95 (dd, J=6.8, 8.9 Hz, 1H), 7.13 (dd, J=1.4, 8.9 Hz, 1H),7.20-7.25 (m, 2H), 7.26-7.32 (m, 2H).

Example 101

[0627]N-[7-(4-Bromo-2-methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[0628] (Yellow Oil)

[0629]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.08 (m, 4H), 0.28-0.46 (m, 4H),0.78-0.89 (m, 2H), 2.48 (s, 3H), 2.95-3.03 (m, 4H), 3.76 (s, 3H), 6.59(dd, J=1.3, 6.8 Hz, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.16 (s, 1H),7.21 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.48 (dd, J=1.3, 8.8 Hz,1H).

Example 102

[0630]N-[7-(2,4-Dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

[0631] After dissolving tert-butylN-[7-(2,4-dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate(150 mg) in N,N-dimethylformamide (3 mL), sodium hydride (60%, 21 mg)was added while cooling on ice, and then 1-iodopropane (0.041 mL) wasadded and the mixture was stirred for 30 minutes. Water was added to thereaction mixture, extraction was performed with ethyl acetate and theextract was washed with brine. The obtained organic layer was dried overanhydrous magnesium sulfate and filtered, and then the solvent wasdistilled off under reduced pressure to obtain a crude product. This wasdissolved in ethyl acetate (1 mL) without purification, a 4 Nhydrochloric acid/ethyl acetate solution (4 mL) was added, and themixture was stirred at room temperature for 2 hours. The reactionmixture was neutralized with 5 N aqueous sodium hydroxide while coolingon ice, and then extraction was performed with ethyl acetate and theorganic layer was washed with water and brine. After drying overanhydrous magnesium sulfate and filtration, the solvent was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography, and the title compound (60 mg) was obtained from then-hexane:ethyl acetate (20:1) fraction as a yellow oil.

[0632]¹H NMR (400 MHz, CDCl₃) δ 0.99 (t, J=7.6 Hz, 3H), 1.63-1.72 (m,2H), 2.45 (s, 3H), 3.20 (t, J=7.6 Hz, 2H), 6.62 (br d, J=6.4 Hz, 1H),7.06 (dd, J=6.4, 8.4 Hz, 1H), 7.36 (dd, J=2.0, 8.4 Hz, 1H), 7.44 (d,J=8.4 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.63-7.69 (m, 1H).

Example 103

[0633]N-[7-(2,4-Dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

[0634]N-[7-(2,4-dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]-N-propylamine(59 mg) was dissolved in tetrahydrofuran (1 mL), and after addingpropionaldehyde (0.035 mL) and 3 M aqueous sulfuric acid (0.16 mL),sodium borohydride (12 mg) was added in five portions while vigorouslystirring on ice, and stirring was continued for 30 minutes. Water wasadded to the reaction mixture, extraction was performed with diethylether and the extract was washed with saturated aqueous sodiumhydrogencarbonate and brine. After drying over anhydrous magnesiumsulfate and filtration, the solvent was concentrated under reducedpressure, the residue was purified by silica gel column chromatography,and the title compound (49 mg) was obtained from the n-hexane:ethylacetate (100:1) fraction as a yellow oil.

[0635]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.6 Hz, 6H), 1.33-1.44 (m,4H), 2.46 (s, 3H), 3.02 (t, J=7.6 Hz, 2H), 6.56 (br d, J=6.4 Hz, 1H),7.03 (dd, J=6.4, 8.4 Hz, 1H), 7.36 (dd, J=2.0, 8.4 Hz, 1H), 7.45 (d,J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H).

[0636] The compounds of Examples 104 to 158 were synthesized accordingto the production method of Examples 102 and 103.

Example 104

[0637]N-Isobutyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

[0638] (Light Yellow Oil)

[0639]¹H NMR (400 MHz, CDCl₃) δ 0.85-0.95 (m, 9H), 1.35-1.45 (m, 2H),1.50-1.60 (m, 1H), 1.99 (s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 2.86 (d,J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 3.68 (s, 3H), 6.47-6.51(m, 1H),6.67 (s, 1H), 6.75 (s, 1H), 7.00-7.06 (m, 1H), 7.38-7.43 (m, 1H)

Example 105

[0640]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

[0641] (Yellow Oil)

[0642]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.01 (m, 2H), 0.27-0.32 (m, 2H),0.80-0.90 (m, 1H), 0.90 (t, J=7.6 Hz, 3H), 1.35-1.45 (m, 2H), 1.99 (s,3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.93 (d, J=6.8 Hz, 2H), 3.10-3.15 (m,2H), 3.68 (s, 3H), 6.49 (dd, J=1.2, 6.8 Hz, 1H), 6.67 (s, 1H) 6.75 (s,1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.43 (dd, J=1.2, 8.8 Hz, 1H).

Example 106

[0643]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)-N-propylamine

[0644] (Light Yellow Oil)

[0645]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.2 Hz, 3H), 1.30-1.44 (m,2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 3.06-3.12 (m, 2H), 3.28(s, 3H), 3.28-3.32 (m, 2H), 3.35-3.40 (m, 2H), 3.68 (s, 3H), 6.51 (dd,J=1.2, 6.8 Hz, 1H), 6.67 (s, 1H). 6.75 (s, 1H), 7.05 (dd, J=6.8, 8.8 Hz,1H), 7.41 (dd, J=1.6, 8.8 Hz, 1H).

Example 107

[0646]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine

[0647] (Light Yellow Oil)

[0648]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.02 (m, 2H), 0.28-0.32 (m, 2H),0.82-0.92 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.98 (d,J=6.8 Hz, 2H), 3.29 (s, 3H), 3.36-3.42 (m, 4H), 3.68 (s, 3H), 6.51 (dd,J=1.2, 6.8 Hz, 1H), 6.67 (s, 1H). 6.76 (s, 1H), 7.05 (dd, J=6.8, 8.8 Hz,1H), 7.44 (dd, J=1.2, 8.8 Hz, 1H).

Example 108

[0649]N-Isobutyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine

[0650] (Light Yellow Oil)

[0651] MS(ESI) m/z 428 MH⁺

Example 109

[0652]N-(3-Fluoropropyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

[0653] (Light Yellow Oil)

[0654]¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=7.2 Hz, 3H), 1.36-1.45 (m,2H), 1.68-1.82 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H),3.01-3.06 (m, 2H), 3.23 (t, J=6.8 Hz, 2H), 3.68 (s, 3H), 4.56 (td,J=6.0, 47.6 Hz, 2H), 6.51 (dd, J=1.6, 6.8 Hz, 1H), 6.67 (s, 1H). 6.75(s, 1H), 7.06 (dd, J=6.8, 8.8 Hz, 1H), 7.37 (dd, J=1.6, 8.8 Hz, 1H).

Example 110

[0655]N-Cyclopropylmethyl-N-(3-fluoropropyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0656] (Light Yellow Oil)

[0657]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.02 (m, 2H), 0.28-0.36 (m, 2H),0.80-0.92 (m, 1H), 1.70-1.84 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43(s, 3H), 2.93 (d, J=6.8 Hz, 2H), 3.31 (t, J=7.6 Hz, 2H), 3.68 (s, 3H),4.57 (td, J=6.0, 47.2 Hz, 2H), 6.50 (dd, J=1.6, 6.8 Hz, 1H), 6.67 (s,1H), 6.76 (s, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.40 (dd, J=1.6, 8.8Hz, 1H).

Example 111

[0658]N-(3-Fluoropropyl)-N-isobutyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0659] (Light Yellow Oil)

[0660] MS(ESI) m/z 430 MH⁺

Example 112

[0661]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

[0662] (Light Yellow Oil)

[0663] MS(ESI) m/z 452 MH⁺

Example 113

[0664]N-Isobutyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

[0665] (Light Yellow Oil)

[0666] MS(ESI) m/z 454 MH⁺

Example 114

[0667]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-morpholinoethyl)-N-propylamine

[0668] (Light Yellow Oil)

[0669] MS(ESI) m/z 469 MH⁺

Example 115

[0670]N1-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N2,N2-dimethyl-N1-propyl-1,2-ethanediamine

[0671] (Light Yellow Oil)

[0672] MS(ESI) m/z 427 MH⁺

Example 116

[0673]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-(2-tetrahydro-1H-1-pyrrolylethyl)amine

[0674] (Light Yellow Oil)

[0675] MS(ESI) m/z 453 MH⁺

Example 117

[0676]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-(2-pyridylmethyl)amine

[0677] (Light Yellow Oil)

[0678] MS(ESI) m/z 447 MH⁺

Example 118

[0679]N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

[0680] (Yellow Oil)

[0681]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.05 (m, 2H), 0.26-0.37 (m, 2H),0.82-0.98 (m, 1H), 0.96 (t, J=7.3 Hz, 3H), 1.38-1.52 (m, 2H), 2.06 (s,6H), 2.47 (s, 3H), 2.98 (d, J=6.8 Hz, 2H), 3.12-3.20 (m, 2H), 3.90 (s,3H), 6.44-6.50 (m, 1H), 6.74 (s, 2H), 7.03-7.12 (m, 1H), 7.44-7.52 (m,1H).

[0682] MS(ESI) m/z 410 MH⁺

Example 119

[0683]N-Isobutyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

[0684] (Yellow Crystals)

[0685]¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=7.4 Hz, 3H), 0.93 (d, J=6.6Hz, 6H), 1.33-1.45 (m, 2H), 1.52-1.64 (m, 1H), 2.01 (s, 6H), 2.41 (s,3H), 2.87 (d, J=7.1 Hz, 2H), 2.98 (t, J=7.4 Hz, 2H), 3.84 (s, 3H), 6.42(dd, J=1.3, 6.8 Hz, 1H), 6.69 (s, 2H), 7.03 (dd, J=6.8, 8.8 Hz, 1H),7.42 (dd, J=1.3, 8.8 Hz, 1H).

[0686] MS(ESI) m/z 412 MH⁺

Example 120

[0687]N-Cyclopropylmethyl-N-isobutyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0688] (Yellow Crystals)

[0689]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.05 (m, 2H), 0.32-0.39 (m, 2H),0.87-0.99 (m, 1H), 1.01 (d, J=6.6 Hz, 6H), 1.60-1.74 (m, 1H), 2.10 (s,6H), 2.49 (s, 3H), 2.96 (d, J=6.8 Hz, 2H), 3.02 (d, J=7.1 Hz, 2H), 3.93(s, 3H), 6.50 (dd, J=1.5, 6.8 Hz, 1H), 6.77 (s, 2H), 7.11 (dd, J=6.8,9.0 Hz, 1H), 7.54 (dd, J=1.4, 8.8 Hz, 1H).

[0690] MS(ESI) m/z 424 MH⁺

Example 121

[0691]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(3-methyl-3-oxetanyl)methyl]amine

[0692] (Light Yellow Oil)

[0693]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.04 (m, 2H), 0.30-0.40 (m, 2H),0.76-0.86 (m, 1H), 0.87 (s, 3H), 1.97 (s, 1.5H), 1.98 (s, 1.5H), 2.40(s, 3H), 2.45 (s, 3H), 2.86-3.01 (m, 2H), 3.20-3.25 (m, 1H), 3.52-3.74(m, 8H), 6.55 (dd, J=1.2, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.11(dd, J=6.8, 8.8 Hz, 1H), 7.44-7.48 (m, 1H)

Example 122

[0694]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

[0695] (Yellow Oil)

[0696]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.02 (m, 2H), 0.29-0.34 (m, 2H),0.80-0.90 (m, 1H), 1.62-1.72 (m, 1H), 1.75-1.85 (m, 2H), 1.86-1.96 (m,1H), 2.43 (m, 3H), 2.44 (s, 3H), 2.96 (d, J=6.8 Hz, 2H), 3.05-3.11 (m,1H), 3.40-3.45 (m, 1H), 3.65-3.72 (m, 4H), 3.80-3.90 (m, 2H), 6.49 (s,2H), 6.57 (dd, J=1.6, 6.8 Hz, 1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.44(dd, J=1.6, 8.8 Hz, 1H)

Example 123

[0697]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0698] (Yellow Oil)

[0699]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.02 (m, 2H), 0.28-0.34 (m, 2H),0.80-0.88 (m, 1H), 1.60-1.70 (m, 1H), 1.88-1.98 (m, 1H), 1.98 (s, 1.5H),1.99 (s, 1.5H), 2.20-2.30 (m, 1H), 2.40 (s, 3H), 2.43 (s, 3H), 2.88-2.92(m, 2H), 3.04-3.10 (m, 1H), 3.20-3.26 (m, 1H), 3.60-3.64 (m, 1H),3.65-3.70 (m, 4H), 3.74-3.84 (m, 2H), 6.50 (dd, J=1.2, 6.8 Hz, 1H), 6.67(s, 1H), 6.75 (s, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.39-7.41 (m, 1H)

Example 124

[0700]N-Ethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0701] (Light Yellow Oil)

[0702]¹H NMR (400 MHz, CDCl₃) δ 0.97 (t, J=7.2 Hz, 3H), 1.55-1.66 (m,1H), 1.87-1.97 (m, 1H), 1.98 (s, 1.5H), 1.99 (s, 1.5H), 2.20-2.28 (m,1H), 2.40 (s, 3H), 2.43 (s, 3H), 3.02 (dd, J=8.4, 12.0 Hz, 1H), 3.10 (q,J=7.2 Hz, 2H), 3.19 (dd, J=6.4, 12.0 Hz, 1H), 3.57 (dd, J=5.6, 8.4 Hz,1H), 3.63-3.71 (m, 4H), 3.72-3.84 (m, 2H), 6.51 (dd, J=1.2, 6.8 Hz, 1H),6.67 (s, 1H), 6.75 (s, 1H), 7.05 (dd, J=6.8, 9.2 Hz, 1H), 7.35 (dd,J=1.6, 9.2 Hz, 1H).

Example 125

[0703]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0704] (Light Yellow Oil)

[0705]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.05 (m, 2H), 0.30-0.38 (m, 2H),0.80-0.90 (m, 1H), 1.55-1.70 (m, 1H), 1.86-1.96 (m, 1H), 2.22-2.30 (m,1H), 2.44 (s, 3H), 2.45 (s, 3H), 2.90 (d, J=6.4 Hz, 2H), 3.04-3.10 (m,1H), 3.21-3.26 (m, 1H), 3.60-3.68 (m, 2H), 3.70 (s, 6H), 3.73-3.84 (m,2H), 6.49 (s, 2H), 6.57-6.60 (m, 1H), 7.02-7.07 (m, 1H), 7.36-7.40 (m,1H).

Example 126

[0706]1-(2-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminoethyl)-2-pyrrolidinone

[0707] (Light Yellow Oil)

[0708]¹H NMR (400 MHz, CDCl₃) δ −0.07-0.03 (m, 2H), 0.27-0.47 (m, 2H),0.78-0.88 (m, 1H), 1.86-1.96 (m, 2H), 1.99 (s, 3H), 2.28-2.36 (m, 2H),2.40 (s, 3H), 2.43 (s, 3H), 2.88-2.98 (m, 2H), 3.32-3.43 (m, 6H), 3.68(s, 3H), 6.51 (dd, J=1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.05(dd, J=6.8, 8.8 Hz, 1H), 7.39 (dd, J=1.3, 8.8 Hz, 1H).

Example 127

[0709]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

[0710] (White Crystals)

[0711]¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=7.3 Hz, 3H), 1.39 (ddq,J=7.3, 7.3, 7.3 Hz, 2H), 1.57-1.67 (m, 1H), 1.87-1.97 (m, 1H), 2.18-2.31(m, 1H), 2.44 (s, 3H), 2.44 (s, 3H), 2.97-3.04 (m, 1H), 3.01 (dd, J=7.3,7.3 Hz, 2H), 3.12-3.20 (m, 1H), 3.55-3.84 (m, 4H), 3.70 (s, 6H), 6.49(s, 2H), 6.58 (dd, J=1.3, 6.8 Hz, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H),7.35 (dd, J=1.3, 8.8 Hz, 1H).

Example 128

[0712]N-[7-(4-Methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

[0713] (Yellow Oil)

[0714]¹H NMR (400 MHz, CDCl₃) δ 0.90 (t, J=7.3 Hz, 3H), 1.32-1.45 (m,2H), 1.56-1.68 (m, 1H), 1.87-2.00 (m, 1H), 2.01 (s, 6H), 2.15-2.30 (m,1H), 2.42 (s, 3H), 2.96-3.06 (m, 3H), 3.17 (dd, J=6.6, 12.0 Hz, 1H),3.59 (dd, J=5.7, 8.4 Hz, 1H), 3.62-3.71 (m, 1H), 3.72-3.84 (m, 2H), 3.85(s, 3H), 6.45 (dd, J=1.4, 6.8 Hz, 1H), 6.69 (s, 2H), 7.05 (dd, J=6.8,8.8 Hz, 1H), 7.36 (dd, J=1.3, 8.9 Hz, 1H).

Example 129

[0715]N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0716] (Yellow Oil)

[0717]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.05 (m, 2H), 0.30-0.38 (m, 2H),0.82-0.94 (m, 1H), 1.62-1.75 (m, 1H), 1.92-2.04 (m, 1H), 2.05 (s, 3H),2.06 (s, 3H), 2.24-2.37 (m, 1H), 2.46 (s, 3H), 2.95 (d, J=6.8 Hz, 2H),3.12 (dd, J=8.7, 12.0 Hz, 1H), 3.29 (dd, J=6.6, 12.0 Hz, 1H), 3.66 (dd,J=5.7, 8.6 Hz, 1H), 3.71 (dd, J=7.4, 8.4 Hz, 1H), 3.81 (dd, J=7.2, 8.8Hz, 1H), 3.84-3.90 (m, 1H), 3.89 (s, 3H), 6.49 (dd, J=1.5, 6.8 Hz, 1H),6.74 (s, 2H), 7.09 (dd, J=6.8, 8.8 Hz, 1H), 7.44 (dd, J=1.5, 8.8 Hz,1H).

Example 130

[0718]N-[7-(4-Methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylmethylamine

[0719] (Yellow Oil)

[0720]¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=7.4 Hz, 3H), 1.32-1.46 (m,2H), 1.58-1.70 (m, 1H), 1.74-1.99 (m, 3H), 2.00 (s, 3H), 2.01 (s, 3H),2.41 (s, 3H), 3.01 (dd, J=6.8, 12.0 Hz, 1H), 3.09 (t, J=7.5 Hz, 2H),3.33 (dd, J=5.6, 12.0 Hz, 1H), 3.64-3.74 (m, 1H), 3.77-3.90 (m, 2H),3.85 (s, 3H), 6.44 (dd, J=1.5, 6.8 Hz, 1H), 6.69 (s, 2H), 7.05 (dd,J=6.8, 8.8 Hz, 1H), 7.43 (dd, J=1.4, 8.8 Hz, 1H).

Example 131

[0721]N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

[0722] (Yellow Oil)

[0723]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.05 (m, 2H), 0.28-0.38 (m, 2H),0.80-0.97 (m, 1H), 1.67-1.78 (m, 1H), 1.79-2.06 (m, 3H), 2.05 (s, 3H),2.06 (s, 3H), 2.46 (s, 3H), 3.02 (d, J=6.8 Hz, 2H), 3.14 (dd, J=7.0,13.0 Hz, 1H), 3.47 (dd, J=5.5, 13.0 Hz, 1H), 3.70-3.80 (m, 1H),3.82-3.98 (m, 2H), 3.89 (s, 3H), 6.48 (dd, J=1.5, 6.8 Hz, 1H), 6.74 (s,2H), 7.09 (dd, J=6.8, 8.8 Hz, 1H), 7.51 (dd, J=1.4, 8.8 Hz, 1H).

Example 132

[0724]N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylmethylamine

[0725] (Yellow Crystals)

[0726]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.1 Hz, 3H), 1.30-1.46 (m,2H), 1.54-1.70 (m, 1H), 1.72-2.00 (m, 3H), 2.43 (s, 3H), 2.95-3.12 (m,3H), 3.25-3.38 (m, 1H), 3.62-3.76 (m, 1H), 3.70 (s, 6H), 3.77-3.90 (m,2H), 6.55 (dd, J=1.4, 6.8 Hz, 1H), 6.67 (s, 2H), 7.04 (dd, J=6.8, 8.9Hz, 1H), 7.43 (dd, J=1.4, 8.9 Hz, 1H)

Example 133

[0727]N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2-furanylmethylamine

[0728] (Yellow Oil)

[0729]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.05 (m, 2H), 0.28-0.36 (m, 2H),0.77-0.92 (m, 1H), 1.62-1.72 (m, 1H), 1.73-1.99 (m, 3H), 2.44 (s, 3H),2.96 (t, J=7.2 Hz, 2H), 3.00-3.12 (m, 1H), 3.35-3.46 (m, 1H), 3.62-3.76(m, 1H), 3.70 (s, 6H), 3.77-3.92 (m, 2H), 6.55 (dd, J=1.3, 6.8 Hz, 1H),6.67 (s, 2H), 7.04 (dd, J=6.9, 8.8 Hz, 1H), 7.46 (dd, J=1.3, 8.8 Hz,1H).

Example 134

[0730]N-(3-Furylmethyl)-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

[0731] (Light Yellow Oil)

[0732]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.3 Hz, 3H), 1.34-1.46 (m,2H), 1.99 (s, 6H), 2.42 (s, 3H), 3.07 (t, J=7.4 Hz, 2H), 3.84 (s, 3H),4.09 (s, 2H), 6.32 (d, J=1.1 Hz, 1H), 6.41 (dd, J=1.3, 6.8 Hz, 1H), 6.68(s, 2H), 7.00 (dd, J=6.8, 8.9 Hz, 1H), 7.23 (s, 1H), 7.25-7.30 (m, 2H).

Example 135

[0733]N-Cyclopropylmethyl-N-(3-furylmethyl)-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0734] (Yellow Oil)

[0735]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.08 (m, 2H), 0.30-0.40 (m, 2H),0.82-0.96 (m, 1H), 2.04 (s, 6H), 2.48 (s, 3H), 3.00 (d, J=6.6 Hz, 2H),3.89 (s, 3H), 4.24 (s, 2H), 6.42 (s, 1H), 6.47 (dd, J=1.3, 6.8 Hz, 1H),6.74 (s, 2H), 7.06 (dd, J=6.8, 8.9 Hz, 1H), 7.30-7.36 (m, 2H), 7.41 (dd,J=1.3, 8.9 Hz, 1H).

Example 136

[0736]N-(3-Furylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

[0737] (Yellow Oil)

[0738]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.4 Hz, 3H), 1.33-1.46 (m,2H), 1.97 (s, 3H), 2.39 (s, 3H), 2.43 (s, 3H), 3.06 (t, J=7.3 Hz, 2H),3.67 (s, 3H), 4.09 (s, 2H), 6.32-6.38 (m, 1H), 6.48 (dd, J=1.3, 6.8 Hz,1H), 6.66 (s, 1H), 6.75 (s, 1H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.20-7.32(m, 3H).

Example 137

[0739]N-Cyclopropylmethyl-N-(3-furylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0740] (Yellow Oil)

[0741]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.06 (m, 2H), 0.28-0.38 (m, 2H),0.80-0.93 (m, 1H), 2.00 (s, 3H), 2.42 (s, 3H), 2.46 (s, 3H), 2.97 (dd,J=2.1, 6.7 Hz, 2H), 3.69 (s, 3H), 4.22 (s, 2H), 6.38-6.42 (m, 1H), 6.51(dd, J=1.5, 6.8 Hz, 1H), 6.69 (s, 1H), 6.78 (s, 1H), 7.05 (dd, J=6.8,8.8 Hz, 1H), 7.26-7.34 (m, 2H), 7.39 (dd, J=1.5, 8.8 Hz, 1H).

Example 138

[0742]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylmethylamine

[0743] (White Crystals)

[0744]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.3 Hz, 3H), 1.40 (ddq,J=7.3, 7.3, 7.3 Hz, 2H), 1.58-1.68 (m, 1H), 1.72-1.98 (m, 3H), 2.44 (s,3H), 2.44 (s, 3H), 2.96-3.04 (m, 1H), 3.07 (dd, J=7.3, 7.3 Hz, 2H),3.31-3.38 (m, 1H), 3.63-3.73 (m, 1H), 3.69 (s, 6H), 3.78-3.89 (m, 2H),6.49 (s, 2H), 6.57 (dd, J=1.3, 6.8 Hz, 1H), 7.04 (dd, J=6.8, 8.8 Hz,1H), 7.41 (dd, J=1.3, 8.8 Hz, 1H).

Example 139

[0745]3-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminotetrahydro-2-furanone

[0746] (White Crystals)

[0747]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.08 (m, 2H), 0.23-0.34 (m, 2H),0.80-0.92 (m, 1H), 1.98 (s, 3H), 2.21-2.47 (m, 2H), 2.40 (s, 3H), 2.43(s, 3H), 3.15-3.23 (m, 1H), 3.25-3.33 (m, 1H), 3.67 (s, 3H), 4.08-4.21(m, 3H), 6.54 (dd, J=1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.10(dd, J=6.8, 8.8 Hz, 1H), 7.65 (dd, J=1.3, 8.8 Hz, 1H).

Example 140

[0748]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0749] (Yellow Oil)

[0750]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.01 (m, 2H), 0.30-0.35 (m, 2H),0.80-0.90 (m, 1H), 1.60-1.70 (m, 1H), 1.88-1.98 (m, 2H), 2.01 (s, 1.5H),2.02 (s, 1.5H), 2.20-2.30 (m, 1H), 2.43 (s, 3H), 2.88-2.92 (m, 2H),3.04-3.10 (m, 1H), 3.20-3.27 (m, 1H), 3.60-3.65 (m, 1H), 3.65-3.70 (m,4H), 3.74-3.85 (m, 2H), 3.84 (s. 3H), 6.42 (d, J=2.0 Hz, 1H), 6.46 (d,J=2.0 Hz, 1H), 6.50 (dd, J=1.2, 6.8 Hz., 1H), 7.05 (dd, J=6.8, 8.8 Hz,1H), 7.37-7.40 (m, 1H)

Example 141

[0751]N-[7-(2,4-Dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

[0752] (Yellow Oil)

[0753]¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=7.6 Hz, 3H), 1.34-1.44 (m,2H), 1.58-1.66 (m, 1H), 1.88-1.96 (m, 1H), 2.01 (s, 1.5H), 2.02 (s,1.5H), 2.20-2.30 (m, 1H), 2.43 (s, 3H), 2.97-3.04 (m, 3H), 3.14-3.20 (m,2H), 3.56-3.60 (m, 1H), 3.63-3.70 (m, 4H), 3.74-3.83 (m, 2H), 3.87 (s,3H), 6.42 (d, J=2.0 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 6.50 (dd, J=1.2,6.8 Hz, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.35 (dd, J=1.2, 8.8 Hz, 1H)

Example 142

[0754]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylamine

[0755] (Light Yellow Crystals)

[0756]¹H NMR (400 MHz, CDCl₃) δ −0.06-0.00 (m, 2H), 0.26-0.35 (m, 2H),0.82-0.90 (m, 1H), 1.57-1.72 (m, 1H), 1.74-1.88 (m, 2H), 1.90-1.99 (m,1H), 2.01 (s, 1.5H), 2.02 (s, 1.5H), 2.44 (s, 3H), 2.97 (d, J=6.8 Hz,2H), 3.05-3.12 (m, 1H), 3.38-3.45 (m, 1H), 3.66 (s, 1.5H), 3.67 (s,1.5H), 3.67-3.72 (m, 2H), 3.80-3.92 (m, 5H), 6.42 (d, J=2.0 Hz, 1H),6.46 (d, J=2.0 Hz, 1H), 6.48-6.52 (m, 1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H),7.42-7.47 (m, 1H).

Example 143

[0757]N-[7-(2,4-Dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylamine

[0758] (Light Yellow Crystals)

[0759]¹H NMR (400 MHz, CDCl₃) δ 0.88 (t, J=7.6 Hz, 3H), 1.35-1.44 (m,2H), 1.58-1.68 (m, 1H), 1.76-1.87 (m, 2H), 1.88-1.99 (m, 1H), 2.01 (s,1.5H), 2.02 (s, 1.5H), 2.43 (s, 3H), 2.98-3.04 (m, 1H), 3.05-3.10 (m,2H), 3.30-3.36 (m, 1H), 3.66 (s, 3H), 3.66-3.72 (m, 1H), 3.80-3.86 (m,2H), 3.87 (s, 3H), 6.42 (d, J=2.0 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 6.50(dd, J=1.6, 6.8 Hz, 1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.40-7.44 (m, 1H)

Example 144

[0760]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-furylmethyl)-amine

[0761] (Yellow Oil)

[0762]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.30-0.37 (m, 2H),0.80-0.92 (m, 1H), 2.44 (s, 3H), 2.46 (s, 3H), 2.95 (d, J=6.8 Hz, 2H),3.69 (s, 6H), 4.21 (s, 2H), 6.38-6.42 (m, 1H), 6.49 (s, 2H), 6.57 (dd,J=1.3, 6.8 Hz, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.28-7.32 (m, 2H),7.37 (dd, J=1.5, 8.8 Hz, 1H)

Example 145

[0763]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

[0764] (Yellow Oil)

[0765]¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=7.2 Hz, 3H), 1.34-1.43 (m,2H), 1.55-1.66 (m, 1H), 1.88-1.98 (m, 1H), 1.99 (s, 1.5H), 2.00 (s,1.5H), 2.20-2.30 (m, 1H), 2.40 (s, 3H), 2.42 (s, 3H), 2.96-3.05 (m, 3H),3.14-3.20 (m, 1H), 3.58 (dd, J=5.6, 8.4 Hz, 1H), 3.63-3.70 (m, 1H), 3.68(s, 3H), 3.74-3.84 (m, 2H), 6.51 (dd, J=1.6, 6.8 Hz, 1H), 6.67 (s, 1H),6.75 (s, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.35 (dd, J=1.6, 6.8 Hz,1H).

Example 146

[0766]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-tetrahydro-2-furanylethyl)amine

[0767] (Yellow Oil)

[0768]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.00 (m, 2H), 0.26-0.32 (m, 2H),0.80-0.90 (m, 1H), 1.38-1.50 (m, 1H), 1.50-1.60 (m, 1H), 1.64-1.76 (m,1H), 1.80-1.90 (m, 1H), 1.91-1.98 (m, 1H), 1.98 (s, 1.5H), 1.99 (s,1.5H), 2.40 (s, 3H), 2.43 (s, 3H), 2.93 (d, J=6.8 Hz, 2H), 3.20-3.34 (m,2H), 3.66-3.73 (m, 1H), 3.68 (s, 3H), 3.80-3.86 (m, 1H), 3.88-3.96 (m,1H), 6.49 (dd, J=1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.03 (dd,J=6.8, 8.8 Hz, 1H), 7.42 (dd, J=1.6, 8.8 Hz, 1H)

Example 147

[0769]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-pyridylmethyl)amine

[0770] (Yellow Oil)

[0771]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.01 (m, 2H), 0.28-0.35 (m, 2H),0.80-0.89 (m, 1H), 1.94 (s, 3H), 2.39 (s, 3H), 2.44 (s, 3H), 2.87-2.97(m, 2H), 3.65 (s, 3H), 4.36 (s, 2H), 6.48 (dd, J=1.3, 6.8 Hz, 1H), 6.66(s, 1H), 6.74 (s, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.17 (dd, J=4.8,8.0 Hz, 1H), 7.38 (dd, J=1.3, 8.8 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 8.42(d, J=4.8 Hz, 1H), 8.61 (s, 1H).

Example 148

[0772]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-furylmethyl)amine

[0773] (Yellow Oil)

[0774]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.06 (m, 2H), 0.28-0.36 (m, 2H),0.80-0.93 (m, 1H), 2.42 (s, 3H), 2.45 (s, 3H), 3.00 (d, J=6.8 Hz, 2H),3.68 (s, 6H), 4.31 (s, 2H), 6.08-6.12 (m, 1H), 6.24 (dd, J=1.8, 3.1 Hz,1H), 6.48 (s, 2H), 6.55 (dd, J=1.4, 6.8 Hz, 1H), 6.99 (dd, J=6.8, 8.9Hz, 1H), 7.24 (dd, J=1.3, 8.8 Hz, 1H), 7.32 (dd, J=0.7, 1.8 Hz, 1H).

Example 149

[0775]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(5-methyl-2-furyl)methyl]amine

[0776] (Yellow Oil)

[0777]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.28-0.36 (m, 2H),0.80-0.93 (m, 1H), 2.22 (s, 3H), 2.42 (s, 3H), 2.45 (s, 3H), 3.00 (d,J=6.8 Hz, 2H), 3.68 (s, 6H), 4.25 (s, 2H), 5.78-5.82 (m, 1H), 5.97 (d,J=3.1 Hz, 1H), 6.48 (s, 2H), 6.55 (dd, J=1.4, 6.9 Hz, 1H), 6.98 (dd,J=6.8, 8.9 Hz, 1H), 7.25 (dd, J=1.4, 8.9 Hz, 1H).

Example 150

[0778]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1H-3-pyrrolylmethyl)amine

[0779] (Yellow Oil)

[0780]¹H NMR (400 MHz, CDCl₃) δ −0.06-−0.03 (m, 2H), 0.28-0.34 (m, 2H),0.78-0.88 (m, 1H), 1.97 (s, 3H), 2.39 (s, 3H), 2.44 (s, 3H), 2.88 (d,J=6.4 Hz, 2H), 3.66 (s, 3H), 4.34 (s, 2H), 6.07-6.10 (m, 1H), 6.09 (dd,J=2.4, 5.6 Hz, 1H), 6.50 (dd, J=1.6, 6.8 Hz, 1H), 6.66 (s, 1H),6.70-6.72 (m, 1H), 6.74 (s, 1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.35 (dd,J=1.6, 8.8 Hz, 1H), 8.70-8.80 (m, 1H).

Example 151

[0781]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1H-4-pyrazolylmethyl)amine

[0782] (Yellow Oil)

[0783]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.02 (m, 2H), 0.33-0.39 (m, 2H),0.82-0.92 (m, 1H), 1.98 (s, 3H), 2.41 (s, 3H), 2.47 (s, 3H), 2.95 (d,J=6.8 Hz, 2H), 3.67 (s, 3H), 4.49 (s, 2H), 6.14 (d, J=1.6 Hz, 1H), 6.53(dd, J=1.2, 6.8 Hz, 1H), 6.68 (s, 1H), 6.70 (s, 1H), 7.08 (dd, J=6.8,8.8 Hz, 1H), 7.39 (dd, J=1.2, 8.8 Hz, 1H), 7.48 (d, J=1.2 Hz, 1H).

Example 152

[0784]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-pyridylmethyl)amine

[0785] (Yellow Oil)

[0786]¹H NMR (400 MHz, CDCl₃) δ −0.06-−0.02 (m, 2H), 0.29-0.36 (m, 2H),0.81-0.90 (m, 1H), 1.95 (s, 3H), 2.39 (s, 3H), 2.44 (s, 3H), 2.83-2.95(m, 2H), 3.65 (s, 3H), 4.37 (s, 2H), 6.49 (dd, J=1.3, 6.8 Hz, 1H), 6.65(s, 1H), 6.73 (s, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.39 (d, J=6.0 Hz,2H), 7.43 (dd, J=1.3, 8.8 Hz, 1H), 8.47 (d, J=6.0 Hz, 2H).

Example 153

[0787]N-Cyclopropylmethyl-N-(2,2-difluoroethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0788] (Yellow Oil)

[0789]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.38 (m, 2H),0.78-0.90 (m, 1H), 1.97 (s, 3H), 2.38 (s, 3H), 2.42 (s, 3H), 2.99 (dd,J=1.6, 6.8 Hz, 2H), 3.49 (dd, J=4.4, 9.6 Hz, 2H), 3.66 (s, 3H), 5.76(tt, J=4.6, 56.4 Hz, 1H), 6.52 (dd, J=1.6, 7.2 Hz, 1H), 6.65 (s, 1H),6.74 (s, 1H), 7.08 (dd, J=6.8, 8.8 Hz, 1H), 7.41 (dd, J=1.6, 8.8 Hz, 1H)

Example 154

[0790]N-(2,2-Difluoroethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0791] (Yellow Oil)

[0792]¹H NMR (400 MHz, CDCl₃) δ 1.58-1.66 (m, 1H), 1.90-1.98 (m, 1H),1.99 (s, 3H), 2.18-2.26 (m, 1H), 2.40 (s, 3H), 2.44 (s, 3H), 3.06-3.14(m, 1H), 3.22-3.28 (m, 1H), 3.36-3.46 (m, 2H), 3.56-3.62 (m, 1H),3.64-3.72 (m, 1H), 3.68 (s, 3H), 3.72-3.84 (m, 2H), 5.74 (tt, J=4.4,56.4 Hz, 1H), 6.56 (dd, J=1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H),7.12 (dd, J=6.8, 8.8 Hz, 1H), 7.36 (dd, J=1.2, 8.8 Hz, 1H).

Example 155

[0793]N-Cyclopropylmethyl-N-[7-[2-(fluoromethoxy)-4,6-dimethylphenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[0794] (Light Yellow Oil)

[0795]¹H NMR (400 MHz, CDCl₃) δ −0.06-0.01 (m, 2H), 0.28-0.35 (m, 2H),0.78-0.88 (m, 1H), 1.59-1.70 (m, 1H), 1.88-1.98 (m, 1H), 2.04 (s, 3H),2.20-2.30 (m, 1H), 2.40 (s, 3H), 2.41 (s, 3H), 2.84-2.94 (m, 2H),3.02-3.10 (m, 1H), 3.20-3.27 (m, 1H), 3.58-3.70 (m, 2H), 3.72-3.85 (m,2H), 5.40 (dd, J=2.4, 75 Hz, 1H), 5.53 (dd, J=2.4, 75 Hz, 1H), 6.50 (dd,J=1.3, 6.8 Hz, 1H), 6.91 (s, 1H), 6.94 (s, 1H), 7.05 (dd, J=6.8, 8.8 Hz,1H), 7.40 (dd, J=1.3, 8.8 Hz, 1H).

Example 156

[0796]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(1-methyl-1H-2-imidazolyl)methyl]amine

[0797] (Light Yellow Amorphous)

[0798]¹H NMR (400 MHz, CDCl₃) δ −0.08-0.02 (m, 2H), 0.23-0.33 (m, 2H),0.75-0.85 (m, 1H), 1.98 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.85-2.91(m, 2H), 3.65 (s, 3H), 3.66 (s, 3H), 4.43 (s, 2H), 6.49 (dd, J=1.3, 6.8Hz, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 6.79 (d, J=1.2 Hz, 1H), 6.91 (d,J=1.2 Hz, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.26 (dd, J=1.3, 8.8 Hz,1H).

Example 157

[0799]N3-Cyclopropylmethyl-N-3-[6-(dimethylamino)-3-pyridyl]methyl-7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

[0800] (Light Yellow Amorphous)

[0801]¹H NMR (400 MHz, CDCl₃) δ −0.12-−0.02 (m, 2H), 0.22-0.32 (m, 2H),0.75-0.86 (m, 1H), 1.95 (s, 3H), 2.39 (s, 3H), 2.43 (s, 3H), 2.80-2.92(m, 2H), 3.04 (s, 6H), 3.65 (s, 3H), 4.19 (s, 2H), 6.44 (d, J=8.0 Hz,1H), 6.47 (dd, J=1.3, 6.8 Hz, 1H), 6.65 (s, 1H), 6.73 (s, 1H), 7.00 (dd,J=6.8, 8.8 Hz, 1H), 7.40 (dd, J=1.3, 8.8 Hz, 1H), 7.53 (dd, J=2.4, 8.0Hz, 1H), 8.11 (d, J=2.4 Hz, 1H).

Example 158

[0802]2-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-1-methylethylbenzoate

[0803] (Yellow Oil)

[0804]¹H NMR (400 MHz, CDCl₃) δ 1.41-1.49 (m, 3H), 1.96 (s, 3H), 2.35(s, 3H), 2.39 (s, 3H), 3.35-3.49 (m, 2H), 3.66 (s, 3H), 5.25-5.36 (m,1H), 6.52 (dd, J=6.8 Hz, 1H), 6.66 (s, 1H), 6.75 (s, 1H), 7.01 (dd,J=6.8, 8.8 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.46 (dd, J=8.0, 8.0 Hz,1H), 7.46 (d, J=8.8 Hz, 1H), 7.57 (dd, J=8.0, 8.0 Hz, 1H), 8.07 (d,J=8.0 Hz, 2H)

Example 159

[0805]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[0806] After dissolvingN-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine(100 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde(78 mg) [CAS No.50675-18-8] and sodium triacetoxyborohydride (87 mg)were added, and the mixture was stirred for 1 hour. Saturated aqueoussodium hydrogencarbonate was added to the reaction mixture, extractionwas performed with ethyl acetate, and the extract was washed with brine.After drying over anhydrous magnesium sulfate and filtration, thesolvent was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography, and the title compound (70mg) was obtained from the n-hexane:ethyl acetate (7:1) fraction as ayellow oil.

[0807]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.00 (m, 2H), 0.27-0.35 (m, 2H),0.80-0.90 (m, 1H), 1.22-1.33 (m, 2H), 1.50-1.62 (m, 1H), 1.75-1.82 (m,2H), 2.00 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.88 (d, J=6.4 Hz, 2H),3.05 (d, J=7.2 Hz, 2H), 3.28-3.35 (m, 2H), 3.69 (s, 3H), 3.90-3.96 (m,2H), 6.50 (dd, J=1.2, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.04 (dd,J=6.8, 8.8 Hz, 1H), 7.40 (dd, J=1.2, 8.8 Hz, 1H).

[0808] The compounds of Examples 160 to 198 were synthesized accordingto the production method of Example 159.

Example 160

[0809]N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylamine

[0810] (Yellow Oil)

[0811]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.26-0.36 (m, 2H),0.72-0.88 (m, 1H), 1.50-1.65 (m, 2H), 1.84-1.94 (m, 2H), 2.49 (s, 3H),3.04 (d, J=6.6 Hz, 2H), 3.30-3.39 (m, 1H), 3.44 (dt, J=1.5, 12.0 Hz,2H), 3.75 (s, 6H), 3.96-4.04 (m, 2H), 6.61 (br d, J=6.8 Hz, 1H), 6.73(s, 2H), 7.10 (dd, J=6.9, 8.9 Hz, 1H), 7.45 (br d, J=8.8 Hz, 1H).

[0812] MS(ESI) m/z 488 MH⁺

Example 161

[0813]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0814] (Light Yellow Amorphous)

[0815]¹H NMR (400 MHz, CDCl₃) δ −0.08-−0.04 (m, 2H), 0.22-0.26 (m, 2H),0.70-0.80 (m, 1H), 1.46-1.60 (m, 2H), 1.80-1.86 (m, 2H), 1.99 (s, 3H),2.40 (s, 3H), 2.43 (s, 3H), 2.99 (d, J=6.4 Hz, 2H), 3.26-3.34 (m, 1H),3.35-3.43 (m, 2H), 3.68 (s, 3H), 3.92-3.98 (m, 2H), 6.50 (dd, J=1.2, 6.8Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.38(dd, J=1.2, 8.8 Hz, 1H).

Example 162

[0816]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

[0817] (Light Yellow Crystals)

[0818]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.2 Hz, 3H), 1.26-1.36 (m,2H), 1.50-1.60 (m, 2H), 1.80-1.86 (m, 2H), 2.40 (s, 3H), 2.42 (s, 3H),3.09 (t, J=6.4 Hz, 2H), 3.16-3.24 (m, 1H), 3.38 (t, J=11.6 Hz, 2H), 3.69(s, 3H), 3.92-3.98 (m, 2H), 6.49-6.52 (m, 1H), 6.67 (s, 1H), 6.75 (s,1H), 7.02-7.08 (m, 1H), 7.34-7.38 (m, 1H).

Example 163

[0819]N-(3-Fluoropropyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0820] (Light Yellow Crystals)

[0821]¹H NMR (400 MHz, CDCl₃) δ 1.50-1.73 (m, 4H), 1.80-1.86 (m, 2H),1.99 (s, 3H), 3.14-3.23 (m, 1H), 3.30 (t, J=6.8 Hz, 2H), 3.37 (dt,J=2.0, 12.0 Hz, 2H), 3.69 (s, 3H), 3.92-4.00 (m, 2H), 4.55 (td, J=5.6,47.6 Hz, 2H), 6.53 (dd, J=1.2, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H),7.07 (dd, J=6.8, 8.8 Hz, 1H), 7.33 (dd, J=1.2, 8.8 Hz, 1H).

Example 164

[0822]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0823] (Light Yellow Amorphous)

[0824]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.00 (m, 2H), 0.24-0.30 (m, 2H),0.70-0.80 (m, 1H), 1.48-1.62 (m, 2H), 1.80-1.86 (m, 2H), 2.44 (s, 3H),2.45 (s, 3H), 2.99 (d, J=6.8 Hz, 2H), 3.25-3.40 (m, 2H), 3.69 (s, 6H),3.90-3.98 (m, 2H), 6.49 (s, 2H), 6.58 (dd, J=1.2, 6.8 Hz, 1H), 7.04 (dd,J=6.8, 8.8 Hz, 1H), 7.37 (dd, J=1.2, 8.8 Hz, 1H).

Example 165

[0825]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

[0826] (Light Yellow Crystals)

[0827]¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7.2 Hz, 3H), 1.28-1.36 (m,2H), 1.49-1.60 (m, 2H), 1.80-1.86 (m, 2H), 2.43 (s, 6H), 3.09 (t, J=7.2Hz, 2H), 3.15-3.24 (m, 1H), 3.33-3.40 (m, 2H), 3.70 (s, 6H), 3.92-3.98(m, 2H), 6.49 (s, 2H), 6.57-6.60 (m, 1H), 7.02-7.06 (m, 1H), 7.32-7.36(m, 1H).

Example 166

[0828]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-tetrahydro-2H-4-pyranylamine

[0829] (Light Yellow Crystals)

[0830]¹H NMR (400 MHz, CDCl₃) δ 1.50-1.73 (m, 4H), 1.80-1.86 (m, 2H),2.42 (s, 1.5H), 2.43 (s, 1.5H), 2.44 (s, 3H), 3.14-3.23 (m, 1H), 3.29(t, J=6.4 Hz, 2H), 3.37 (t, J=12.0 Hz, 2H), 3.70 (s, 6H), 3.92-3.99 (m,2H), 4.54 (td, J=5.6, 47.6 Hz, 2H), 6.49 (s, 2H), 6.58-6.62 (m, 1H),7.04-7.08 (m, 1H), 7.29-7.33 (m, 1H).

Example 167

[0831]N-[7-(4-Methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

[0832] (Yellow Oil)

[0833]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.3 Hz, 3H), 1.24-1.37 (m,2H), 1.46-1.60 (m, 2H), 1.78-1.86 (m, 2H), 2.01 (s, 6H), 2.40 (s, 3H),3.09 (t, J=7.2 Hz, 2H), 3.15-3.25 (m, 1H), 3.38 (dt, J=2.0, 12.0 Hz,2H), 3.85 (s, 3H), 3.92-3.99 (m, 2H), 6.44 (dd, J=1.5, 6.8 Hz, 1H), 6.69(s, 2H), 7.05 (dd, J=6.8, 9.0 Hz, 1H), 7.37 (dd, J=1.4, 8.9 Hz, 1H).

[0834] MS(ESI) m/z 440 MH⁺

Example 168

[0835]N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0836] (Yellow Crystals)

[0837]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.28-0.37 (m, 2H),0.78-0.90 (m, 1H), 1.55-1.68 (m, 2H), 1.89-1.98 (m, 2H), 2.11 (s, 6H),2.51 (s, 3H), 3.09 (d, J=6.6 Hz, 2H), 3.35-3.45 (m, 1H), 3.49 (dt,J=2.0, 12.0 Hz, 2H), 3.95 (s, 3H), 4.02-4.09 (m, 2H), 6.54 (dd, J=1.4,6.6 Hz, 1H), 6.79 (s, 2H), 7.15 (dd, J=6.7, 8.9 Hz, 1H), 7.49 (dd,J=1.4, 8.9 Hz, 1H).

[0838] MS(ESI) m/z 452 MH⁺

Example 169

[0839]N-(3-Fluoropropyl)-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0840] (Light Brown Oil)

[0841]¹H NMR (400 MHz, CDCl₃) δ 1.48-1.65 (m, 2H), 1.66-1.74 (m, 2H),1.78-1.87 (m, 2H), 2.01 (s, 6H), 2.40 (s, 3H), 3.14-3.24 (m, 1H), 3.29(t, J=6.6 Hz, 2H), 3.37 (dt, J=2.0, 12.0 Hz, 2H), 3.85 (s, 3H),3.92-4.00 (m, 2H), 4.49 (t, J=5.8 Hz, 1H), 4.61 (t, J=5.8 Hz, 1H), 6.46(dd, J=1.5, 6.8 Hz, 1H), 6.69 (s, 2H), 7.07 (dd, J=6.8, 8.8 Hz, 1H),7.34 (dd, J=1.4, 8.8 Hz, 1H).

[0842] MS(ESI) m/z 458 MH⁺

Example 170

[0843]N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-tetrahydro-2H-4-pyranylamine

[0844] (Yellow Crystals)

[0845]¹H NMR (400 MHz, CDCl₃) δ 1.48-1.65 (m, 2H), 1.66-1.74 (m, 2H),1.78-1.87 (m, 2H), 2.42 (s, 3H), 3.16-3.23 (m, 1H), 3.28 (t, J=6.6 Hz,2H), 3.36 (dt, J=1.8, 12.0 Hz, 2H), 3.70 (s, 6H), 3.90-4.00 (m, 2H),4.48 (t, J=5.8 Hz, 1H), 4.60 (t, J=5.8 Hz, 1H), 6.57 (dd, J=1.4, 6.9 Hz,1H), 6.67 (s, 2H), 7.06 (dd, J=6.8, 8.8 Hz, 1H), 7.33 (dd, J=1.4, 8.8Hz, 1H).

Example 171

[0846]N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

[0847] (Yellow Crystals)

[0848]¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7.4 Hz, 3H), 1.25-1.38 (m,2H), 1.47-1.60 (m, 2H), 1.78-1.87 (m, 2H), 2.42 (s, 3H), 3.08 (t, J=7.3Hz, 2H), 3.14-3.24 (m, 1H), 3.37 (dt, J=2.0, 12.0 Hz, 2H), 3.70 (s, 6H),3.91-3.99 (m, 2H), 6.55 (dd, J=1.4, 6.9 Hz, 1H), 6.67 (s, 2H), 7.04 (dd,J=6.8, 8.8 Hz, 1H), 7.36 (dd, J=1.4, 8.8 Hz, 1H).

[0849] MS(ESI) m/z 476 MH⁺

Example 172

[0850]N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylamine

[0851] (Light Green Crystals)

[0852]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.00 (m, 2H), 0.20-0.26 (m, 2H),0.70-0.90 (m, 1H), 1.50-1.62 (m, 2H), 1.80-1.88 (m, 2H), 2.42 (s, 3H),2.43 (s, 3H), 2.99 (d, J=6.8 Hz, 2H), 3.25-3.44 (m, 3H), 3.70 (s, 3H),3.90-3.95 (m, 2H), 6.56 (dd, J=1.6, 7.2 Hz, 1H), 6.73 (s, 1H), 6.96 (d,J=0.8 Hz, 1H), 7.06 (dd, J=7.2, 9.2 Hz, 1H), 7.42 (dd, J=1.6, 8.8 Hz,1H).

Example 173

[0853]N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

[0854] (Light Yellow Crystals)

[0855]¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7.2 Hz, 3H), 1.25-1.36 (m,2H), 1.50-1.70 (m, 2H), 1.78-1.88 (m, 2H), 2.41 (s, 3H), 2.42 (s, 3H),3.09 (t, J=7.6 Hz, 2H), 3.15-3.22 (m, 1H), 3.34-3.40 (m, 2H), 3.70 (s,3H), 3.93-3.96 (m, 2H), 6.56 (dd, J=1.2, 6.8 Hz, 1H), 6.73 (s, 1H), 6.96(br s, 1H), 7.06 (dd, J=7.2, 9.2 Hz, 1H), 7.39 (dd, J=1.6, 8.8 Hz, 1H)

Example 174

[0856]N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1-methyl-4-piperidyl)amine

[0857] (Yellow Crystals)

[0858]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.27-0.36 (m, 2H),0.78-0.92 (m, 1H), 1.56-1.68 (m, 2H), 1.83-1.93 (m, 1H), 1.98-2.10 (m,3H), 2.11 (s, 6H), 2.33 (s, 3H), 2.51 (s, 3H), 2.88-2.97 (m, 2H), 3.10(d, J=6.6 Hz, 2H), 3.12-3.22 (m, 1H), 3.95 (s, 3H), 6.53 (dd, J=1.4, 6.7Hz, 1H), 6.79 (s, 2H), 7.13 (dd, J=6.8, 8.8 Hz, 1H), 7.49 (dd, J=1.4,8.8 Hz, 1H)

[0859] MS(ESI) m/z 465 MH⁺

Example 175

[0860]1-(4-(Cyclopropylmethyl)[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminopiperidino)-1-ethanone

[0861] (Light Yellow Oil)

[0862]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.28-0.38 (m, 2H),0.78-0.90 (m, 1H), 1.43-1.56 (m, 2H), 1.97-2.08 (m, 2H), 2.11 (s, 3H),2.13 (s, 3H), 2.15 (s, 3H), 2.52 (s, 3H), 2.86 (dt, J=2.8, 14.0 Hz, 1H),3.09 (d, J=6.6 Hz, 2H), 3.19 (dt, J=2.8, 14.0 Hz, 1H), 3.38-3.50 (m,1H), 3.82-3.92 (m, 1H), 3.95 (s, 3H), 4.48-4.58 (m, 1H), 6.56 (dd,J=1.5, 6.8 Hz, 1H), 6.80 (s, 2H), 7.16 (dd, J=6.8, 8.8 Hz, 1H), 7.47(dd, J=1.5, 8.8 Hz, 1H).

[0863] MS(ESI) m/z 493 MH⁺

Example 176

[0864]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-thiophenylamine

[0865] (Light Yellow Oil)

[0866]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.06 (m,2H), 0.26-0.36 (m, 2H),0.78-0.88 (m, 1H), 1.85-1.95 (m, 1H), 2.03 (s, 1.5H), 2.04 (s, 1.5H),2.15-2.25 (m, 1H), 2.46 (s, 3H), 2.49 (s, 3H), 2.76-2.84 (m, 1H),2.85-2.92 (m, 2H), 2.93-3.01 (m, 1H), 3.02-3.08 (m, 2H), 3.74 (s, 3H),4.01-4.12 (m, 1H), 6.57 (dd, J=1.4, 6.8 Hz, 1H), 6.73 (s, 1H), 6.81 (s,1H), 7.12 (dd, J=6.8, 8.8 Hz, 1H), 7.46 (dd, J=1.4, 8.8 Hz, 1H)

Example 177

[0867]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

[0868] (Yellow Solid)

[0869]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.26-0.36 (m, 2H),0.78-0.88 (m, 1H), 1.32-1.44 (m, 1H), 1.62-1.78 (m, 2H), 2.06 (s, 3H),2.04-2.18 (m, 1H), 2.48 (s, 3H), 2.50 (s, 3H), 2.98-3.10 (m, 2H),3.20-3.38 (m, 3H), 3.76 (s, 3H), 3.82-3.92 (m, 1H), 4.12-4.22 (m, 1H),6.60 (dd, J=1.6, 7.2 Hz, 1H), 6.75 (s, 1H), 6.83 (s, 1H), 7.15 (dd,J=7.2, 8.8 Hz, 1H), 7.45 (dd, J=1.6, 8.8 Hz, 1H).

[0870] MS (ESI)m/z 452 MH⁺

Example 178

[0871]N-(3-Furylmethyl)-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0872] (Yellow Oil)

[0873]¹H NMR (400 MHz, CDCl₃) δ 1.50-1.66 (m, 2H), 1.84-1.94 (m, 2H),1.97 (s, 6H), 2.40 (s, 3H), 3.24-3.34 (m, 1H), 3.39 (t, J=12.0 Hz, 2H),3.84 (s, 3H), 3.92-4.02 (m, 2H), 4.20 (s, 2H), 6.28 (s, 1H), 6.42 (d,J=6.6 Hz, 1H), 6.68 (s, 2H), 7.03 (dd, J=6.8, 8.7 Hz, 1H), 7.17-7.30 (m,3H).

Example 179

[0874]N-(3-Furylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0875] (Yellow Amorphous)

[0876]¹H NMR (400 MHz, CDCl₃) δ 1.50-1.66 (m, 2H), 1.82-1.94 (m, 2H),1.95 (s, 3H), 2.39 (s, 3H), 2.41 (s, 3H), 3.22-3.33 (m, 1H), 3.38 (br t,J=12.0 Hz, 2H), 3.66 (s, 3H), 3.90-4.02 (m, 2H), 4.20 (s, 2H), 6.28-6.33(m, 1H), 6.49 (dd, J=1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 7.03(dd, J=6.8, 8.9 Hz, 1H), 7.18-7.30 (m, 3H).

Example 180

[0877]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethyl-N-tetrahydro-2H-4-pyranylamine

[0878] (White Crystals)

[0879]¹H NMR (400 MHz, CDCl₃) δ 1.47-1.66 (m, 4H), 1.73-1.94 (m, 4H),2.43 (s, 3H), 2.44 (s, 3H), 2.97-3.05 (m, 1H), 3.15-3.25 (m, 1H),3.30-3.47 (m, 3H), 3.62-3.85 (m, 3H), 3.70 (s, 6H), 3.90-3.99 (m, 2H),6.49 (s, 2H), 6.59 (dd, J=1.3, 6.8 Hz, 1H), 7.05 (dd, J=6.8, 8.8 Hz,1H), 7.35 (dd, J=1.3, 8.8 Hz, 1H).

Example 181

[0880]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylamine

[0881] (White Solid)

[0882]¹H NMR (400 MHz, CDCl₃) δ −0.15-−0.03 (m, 2H), 0.18-0.31 (m, 2H),0.70-0.81 (m, 1H), 1.78-2.05 (m, 2H), 1.98 (s, 3H), 2.40 (s, 3H), 2.44(s, 3H), 2.80-2.98 (m, 2H), 3.55-3.67 (m, 1H), 3.68 (s, 3H), 3.75-3.95(m, 3H), 4.08-4.18 (m, 1H), 6.52 (d, J=6.8 Hz, 1H), 6.68 (s, 1H), 6.76(s, 1H), 7.07 (dd, J=6.8, 8.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H).

Example 182

[0883]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanyl-N-tetrahydro-3-furanylmethylamine

[0884] (White Solid)

[0885]¹H NMR (400 MHz, CDCl₃) δ 1.54-1.68 (m, 1H), 1.76-2.18 (m, 4H),1.98 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.98-3.24 (m, 2H), 3.49-4.07(m, 9H), 3.68 (s, 3H), 6.54 (d, J=6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s,1H), 7.09 (dd, J=6.8, 8.8 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H).

Example 183

[0886]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

[0887] (Yellow Oil)

[0888]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.34 (m, 2H),0.74-0.84 (m, 1H), 1.28-1.38 (m, 1H), 1.60-1.70 (m, 2H), 2.04-2.12 (m,1H), 2.48 (s, 3H), 2.49 (s, 3H), 2.98-3.06 (m, 2H), 3.20-3.34 (m, 3H),3.74 (s, 6H), 3.80-3.86 (m, 1H), 4.10-4.18 (m, 1H), 6.54 (s, 2H), 6.64(dd, J=1.2, 6.8 Hz, 1H), 7.10 (dd, J=6.8, 8.8 Hz, 1H), 7.40 (dd, J=1.2,8.8 Hz, 1H)

Example 184

[0889]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

[0890] (Yellow Oil)

[0891]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.34 (m, 2H),0.76-0.86 (m, 1H), 1.30-1.42 (m, 1H), 1.60-1.74 (m, 2H), 2.06-2.16 (m,1H), 2.50 (s, 3H), 3.00-3.10 (m, 2H), 3.20-3.38 (m, 3H), 3.74 (s, 3H),3.84-3.90 (m, 1H), 3.94 (s, 3H), 4.12-4.20 (m, 1H), 6.50 (s, 1H), 6.53(s, 1H), 6.58 (dd, J=1.2, 7.2 Hz, 1H), 7.12 (dd, J=7.2, 8.8 Hz, 1H),7.43 (dd, J=1.2, 8.8 Hz, 1H).

Example 185

[0892]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0893] (Yellow Oil)

[0894]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.26-0.34 (m, 2H),0.78-0.88 (m, 1H), 1.52-1.68 (m, 2H), 1.86-1.96 (m, 2H), 2.09 (s, 3H),2.51 (s, 3H), 3.02-3.10 (m, 2H), 3.32-3.40 (m, 1H), 3.40-3.50 (m, 2H),3.75 (s, 3H), 3.94 (s, 3H), 3.98-4.08 (m, 2H), 6.49 (s, 1H), 6.54 (s,1H), 6.58 (dd, J=1.2, 6.8 Hz, 1H), 7.12 (dd, J=6.8, 8.8 Hz, 1H), 7.46(dd, J=1.2, 8.8 Hz, 1H).

Example 186

[0895]N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

[0896] (Yellow Oil)

[0897]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.36 (m, 2H),0.78-0.88 (m, 1H), 1.32-1.44 (m, 1H), 1.66-1.78 (m, 2H), 2.10 (s, 6H),2.10-2.18 (m, 1H), 2.50 (s, 3H), 3.02-3.12 (m, 2H), 3.24-3.40 (m, 3H),3.84-3.94 (m, 1H), 3.94 (s, 3H), 4.14-4.20 (m, 1H), 6.50 (dd, J=1.2, 6.8Hz, 1H), 6.78 (s, 2H), 7.15 (dd, J=6.8, 8.8 Hz, 1H), 7.48 (dd, J=1.2,8.8 Hz, 1H).

Example 187

[0898]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[0899] (Yellow Oil)

[0900]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.00 (m, 2H), 0.32-0.38 (m, 2H),0.82-0.92 (m, 1H), 1.24-1.35 (m, 2H), 1.55-1.60 (m, 1H), 1.87-1.95 (m,2H), 2.46 (s, 6H), 2.90 (d, J=6.8 Hz, 2H), 3.06 (d, J=7.2 Hz, 2H), 3.32(dt, J=2.0, 12.0 Hz, 2H), 3.72 (s, 6H), 3.92-3.98 (m, 2H), 6.52 (s, 2H),6.60 (dd, J=1.6, 6.8 Hz, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.41 (dd,J=1.6, 8.8 Hz, 1H).

Example 188

[0901]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethyl-N-tetrahydro-2H-4-pyranylamine

[0902] (White Amorphous)

[0903]¹H NMR (400 MHz, CDCl₃) δ 1.48-1.65 (m, 2H), 1.74-1.95 (m, 4H),1.99 (s, 3H), 2.09-2.19 (m, 1H), 2.40 (s, 3H), 2.42 (s, 3H), 3.01-3.25(m, 3H), 3.31-3.41 (m, 2H), 3.54-3.84 (m, 4H), 3.69 (s, 3H), 3.91-4.00(m, 2H), 6.52 (dd, J=1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.07(dd, J=6.8, 8.8 Hz, 1H), 7.31 (dd, J=1.3, 8.8 Hz, 1H).

Example 189

[0904]N-Cyclopropylmethyl-N-(3,4-dihydro-2H-2-pyranylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0905] (Yellow Oil)

[0906]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.00 (m, 2H), 0.28-0.34 (m, 2H),0.83-0.92 (m, 1H), 1.58-1.70 (m, 1H), 1.90-2.04 (m, 2H), 1.99 (s, 1.5H),2.01 (s, 1.5H), 2.04-2.13 (m, 1H), 2.40 (s, 3H), 2.42 (s, 3H), 2.97 (d,J=6.8 Hz, 2H), 3.17-3.23 (m, 1H), 3.46-3.52 (m, 1H), 3.69 (s, 1.5H),3.70 (s, 1.5H), 3.77-3.83 (m, 1H), 4.60-4.65 (m, 1H), 6.33 (br d, J=6.4Hz, 1H), 6.50-6.53 (m, 1H), 6.65 (br s, 1H), 6.74 (br s, 1H), 7.03-7.08(m, 1H), 7.43-7.47 (m, 1H).

Example 190

[0907]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(2-methoxy-3-pyridyl)methyl]amine

[0908] (Yellow Oil)

[0909]¹H NMR (400 MHz, CDCl₃) δ −0.08-0.02 (m, 2H), 0.27-0.37 (m, 2H),0.82-0.93 (m, 1H), 1.96 (s, 3H), 2.39 (s, 3H), 2.43 (s, 3H), 2.88-3.00(m, 2H), 3.66 (s, 3H), 3.92 (s, 3H), 4.34 (s, 2H), 6.48 (dd, J=1.3, 6.8Hz, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 6.82 (dd, J=4.8, 7.2 Hz, 1H), 7.02(dd, J=6.8, 8.8 Hz, 1H), 7.41 (dd, J=1.3, 8.8 Hz, 1H), 7.86 (dd, J=2.0,7.2 Hz, 1H), 7.99 (dd, J=2.0, 4.8 Hz, 1H).

Example 191

[0910]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranyl-N-tetrahydro-2H-4-pyranylmethylamine

[0911] (White Amorphous)

[0912]¹H NMR (400 MHz, CDCl₃) δ 1.16-1.28 (m, 2H), 1.39-1.65 (m, 3H),1.71-1.86 (m, 4H), 2.43 (s, 3H), 2.44 (s, 3H), 2.98-3.15 (m, 3H),3.22-3.40 (m, 4H), 3.71 (s, 6H), 3.86-3.99 (m, 4H), 6.50 (s, 2H), 6.60(d, J=6.8 Hz, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H).

Example 192

[0913]N-(2,2-Difluoroethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[0914] (White Solid)

[0915]¹H NMR (400 MHz, CDCl₃) δ 1.44-1.58 (m, 2H), 1.80-1.86 (m, 2H),1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 3.18-3.28 (m, 1H), 3.32-3.42(m, 2H), 3.44-3.54 (m, 2H), 3.68 (s, 3H), 3.92-3.98 (m, 2H), 5.67(tt,J=4.4, 56.4 Hz, 1H), 6.56 (dd, J=1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76(s, 1H), 7.12 (dd, J=6.8, 8.8 Hz, 1H), 7.35 (dd, J=1.6, 8.8 Hz, 1H).

Example 193

[0916]N-(2,2-Difluoroethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[0917] (Brown Oil)

[0918]¹H NMR (400 MHz, CDCl₃) δ 1.20-1.32 (m, 2H), 1.50-1.62 (m, 1H),1.76-1.82 (m, 2H), 2.00 (s, 3H), 2.41 (s, 3H), 2.45 (s, 3H), 3.06 (d,J=7.2, 2H), 3.28-3.48 (m, 4H), 3.69 (s, 3H), 3.92-3.98 (m, 2H), 5.74(tt,J=4.4, 56.4 Hz, 1H), 6.56 (dd, J=1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76(s, 1H), 7.11 (dd, J=6.8, 8.8 Hz, 1H), 7.36 (dd, J=1.2, 8.8 Hz, 1H).

Example 194

[0919]N-Butyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[0920] (Yellow Oil)

[0921]¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J=7.2 Hz, 3H), 1.19-1.40 (m,6H), 1.48-1.60 (m, 1H), 1.74-1.80 (m, 2H), 2.43 (s, 6H), 2.95 (d, J=6.8Hz, 2H), 3.01 (t, J=6.8 Hz, 2H), 3.30 (dt, J=2.0, 11.6 Hz, 2H), 3.70 (s,3H), 3.88-3.95 (m, 2H), 6.48 (s, 2H), 6.57 (dd, J=1.6, 7.2 Hz, 1H), 7.02(dd, J=7.2, 8.8 Hz, 1H), 7.33 (dd, J=1.6, 8.8 Hz, 1H).

Example 195

[0922]N-Cyclobutylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[0923] (Yellow Oil)

[0924]¹H NMR (400 MHz, CDCl₃) δ 1.18-1.29 (m, 2H), 1.48-1.63 (m, 3H),1.70-1.80 (m, 4H), 1.81-1.90 (m, 2H), 2.30-2.40 (m, 1H), 2.43 (s, 3H),2.44 (s, 3H), 2.93 (d, J=6.8 Hz, 2H), 3.04 (d, J=7.0 Hz, 2H), 3.30 (dt,J=2.0, 12.0 Hz, 2H), 3.69 (s, 6H), 3.89-3.94 (m, 2H), 6.48 (s, 2H), 6.57(dd, J=1.6, 6.8 Hz, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.31 (dd, J=1.6,8.8 Hz, 1H)

Example 196

[0925]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylmethylamine

[0926] (Yellow Oil)

[0927]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.28-0.42 (m, 2H),0.82-0.92 (m, 1H), 1.22-1.32 (m, 1H), 1.52-1.66 (m, 2H), 1.72-1.80 (m,1H), 1.86-1.94 (m, 1H), 2.04 (br s, 3H), 2.45 (br s, 3H), 2.47 (br s,3H), 2.86-2.94 (m, 2H), 2.96-3.04 (m, 1H), 3.14-3.22 (m, 1H), 3.24-3.30(m, 1H), 3.40-3.46 (m, 1H), 3.72 (br s, 3H), 3.84-3.90 (m, 1H),4.12-4.18 (m, 1H), 6.54 (dd, J=1.6, 6.8 Hz, 1H), 6.71 (s, 1H), 6.79 (s,1H), 7.07 (dd, J=6.8, 8.8 Hz, 1H), 7.44 (dd, J=1.6, 8.8 Hz, 1H)

[0928] MS(ESI) m/z 466 MH⁺

Example 197

[0929]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylmethylamine

[0930] (Yellow Oil)

[0931] H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.30-0.36 (m, 2H),0.80-0.90 (m, 1H), 1.18-1.28 (m, 1H), 1.52-1.60 (m, 2H), 1.66-1.76 (m,1H), 1.82-1.90 (m, 1H), 2.45 (s, 6H), 2.84-2.92 (m, 2H), 2.94-2.98 (m,1H), 3.10-3.18 (m, 1H), 3.18-3.26 (m, 1H), 3.36-3.44 (m, 1H), 3.70 (s,6H), 3.80-3.86 (m, 1H), 4.08-4.12 (m, 1H), 6.49 (s, 2H), 6.57 (dd,J=1.6, 8.8 Hz, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.39 (dd, J=1.6, 8.8Hz, 1H)

Example 198

[0932]N-Cyclopropylmethyl-N-(5,6-dihydro-2H-3-pyranylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0933] (Yellow Oil)

[0934]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.38 (m, 2H),0.80-0.88 (m, 1H), 2.01 (s, 3H), 2.06-2.14 (m, 2H), 2.44 (s, 3H), 2.47(s, 3H), 2.84-2.96 (m, 2H), 3.71 (s, 3H), 3.71-3.76 (m, 4H), 4.30-4.34(m, 2H), 5.75 (br s, 1H), 6.53 (dd, J=1.6, 6.8 Hz, 1H), 6.70 (s, 1H),6.78 (s, 1H), 7.07 (dd, J=6.8, 8.8 Hz, 1H), 7.44 (dd, J=1.6, 8.8 Hz, 1H)

[0935] MS (ESI)m/z 464 MH⁺

Example 199

[0936]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)amine

[0937] After dissolving tert-butylN-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate(100 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 15 mg)was added while cooling on ice, the mixture was stirred for 30 minutes,2-oxetanylmethyl 4-methyl-1-benzenesulfonate (70 mg) was added and themixture was stirred for 1 hour at 40° C. 2-Oxetanylmethyl4-methyl-1-benzenesulfonate (23 mg) [CAS No.115845-51-7] and sodiumhydride (60%, 5 mg) were again added, and the mixture was stirred for 1hour. Water was added to the reaction mixture, extraction was performedwith ethyl acetate and the extract was washed with brine. After dryingthe obtained organic layer over anhydrous magnesium sulfate andfiltering it, the solvent was concentrated under reduced pressure toobtain crude tert-butylN-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)carbamate.This was dissolved in ethyl acetate (2 mL) without purification, a 4 Nhydrochloric acid/ethyl acetate solution (1 mL) was added, and themixture was stirred at room temperature for 1 hour. The reaction mixturewas neutralized with 5 N aqueous sodium hydroxide while cooling on ice,and then extraction was performed with ethyl acetate and the organiclayer was washed with brine. After drying the obtained organic layerover anhydrous magnesium sulfate and filtering it, the solvent wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography, and the title compound (8 mg) was obtainedfrom the n-hexane:ethyl acetate (3:1) fraction as a yellow oil.

[0938]¹H NMR (400 MHz, CDCl₃) δ 1.94-2.04 (m, 1H), 2.00 (s, 3H),2.24-2.34 (m, 1H), 2.40 (s, 3H), 2.44 (s, 3H), 3.24-3.35 (m, 2H),3.49-3.62 (m, 2H), 4.46-4.54 (m, 1H), 6.48-6.54 (m, 1H), 6.67 (s, 1H),6.75 (s, 1H), 7.00-7.06 (m, 1H), 7.44-7.50 (m, 1H).

[0939] MS(ESI) m/z 383 MH⁺

Example 200

[0940]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)amine

[0941] After dissolvingN-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)amine(8 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 1.6 mg) wasadded while cooling on ice, and then cyclopropylmethyl bromide (3.8 μL)was added and the mixture was stirred at room temperature for 12 hours.Water was added to the reaction mixture, extraction was performed withethyl acetate and the extract was washed with brine. After drying overanhydrous magnesium sulfate and filtration, the solvent was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography, and the title compound (1.8 mg) was obtained from then-hexane:ethyl acetate (10:1) fraction as a yellow oil.

[0942]¹H NMR (400 MHz, CDCl₃) δ 0.22-0.26 (m, 2H), 0.54-0.60 (m, 2H),1.06-1.16 (m, 1H), 1.99 (s, 1.5H), 2.00 (s, 1.5H), 2.00-2.08 (m, 1H),2.16-2.26 (m, 1H), 2.39 (s, 3H), 2.43 (br s, 3H), 3.28-3.40 (m, 4H),3.44-3.50 (m, 1H), 3.56-3.64 (m, 1H), 3.67 (s, 3H), 4.20-4.26 (m, 1H),6.45-6.52 (m, 1H), 6.66 (s, 1H), 6.75 (s, 1H), 6.97-7.04 (m, 1H),7.50-7.56 (m, 1H).

[0943] The compound of Example 201 was synthesized according to theproduction method of Examples 199 and 200.

Example 201

[0944]N-Cyclopropylmethyl-N-(1,3-dioxolan-2-ylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0945] (Yellow Oil)

[0946]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.24-0.36 (m, 2H),0.82-0.94 (m, 1H), 2.00 (s, 3H), 2.41 (s, 3H), 2.45 (s, 3H), 3.00-3.08(m, 2H), 3.39 (d, J=4.0 Hz, 2H), 3.68 (s, 3H), 3.80-3.90 (m, 2H),3.92-4.00 (m, 2H), 5.00 (t, J=4.0 Hz, 1H), 6.51 (dd, J=1.2, 6.8 Hz, 1H),6.67 (s, 1H), 6.75 (s, 1H), 7.06 (dd, J=6.8, 8.8 Hz, 1H), 7.47 (dd,J=1.6, 8.8 Hz, 1H).

[0947] MS(ESI) m/z 454 MH⁺

Example 202

[0948]1-[(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-2-propanol

[0949] (Yellow Oil)

[0950] Cyclopropanecarboxyaldehyde (0.047 mL) and 3 M sulfuric acid(0.21 mL) were added to a solution of2-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-1-methylethylbenzoate (100 mg) in tetrahydrofuran (0.7 mL) while cooling on ice, andthen sodium borohydride (16 mg) was slowly added thereto at the sametemperature. The mixture was stirred for 30 minutes at room temperature,and then 5 N aqueous sodium hydroxide (0.3 mL) was added while coolingon ice to make the reaction mixture basic. Methanol (2.1 mL) was addedto the reaction mixture, and after heating to reflux for 1 hour, it wasreturned to room temperature, extraction was performed with ethylacetate, and the extract was washed with brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate:n-hexane=1:5) to obtain the title compound (80 mg) as a yellowoil.

[0951]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.07 (m, 2H), 0.32-0.45 (m, 2H),0.83-0.92 (m, 1H), 1.08-1.14 (m, 3H), 1.98 (s, 3H), 2.40 (s, 3H), 2.44(s, 3H), 2.69-2.78 (m, 1H), 2.83-2.91 (m, 1H), 2.96-3.04 (m, 1H),3.42-3.50 (m, 1H), 3.56-3.68 (m, 1H), 3.68 (s, 3H), 6.54 (dd, J=1.3, 6.8Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.09 (dd, J=6.8, 8.8 Hz, 1H), 7.39(dd, J=1.3, 8.8 Hz, 1H).

Example 203

[0952]1-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-3-fluoro-2-propanol

[0953] (Brownish Oil)

[0954] p-Toluenesulfonic acid hydrate (40 mg) and epifluorohydrin (0.15mL) [CAS No.503-09-3] were added to a solution ofN-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine(50 mg) in 1,2-dimethoxyethane (0.40 mL), and the mixture was heated toreflux for 3 hours. After cooling to room temperature, the solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby basic silica gel column chromatography (ethyl acetate:n-hexane=1:5)to obtain the title compound (24 mg) as a brownish oil.

[0955]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.09 (m, 2H), 0.34-0.46 (m, 2H),0.84-0.94 (m, 1H), 1.99 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.87-2.94(m, 1H), 2.97-3.04 (m, 1H), 3.06-3.14 (m, 1H), 3.48-3.55 (m, 1H), 3.68(s, 3H), 3.68-3.79 (m, 2H), 4.30-4.57 (m, 2H), 6.55 (dd, J=1.3, 6.8 Hz,1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.11 (dd, J=6.8, 8.8 Hz, 1H), 7.39 (dd,J=1.3, 8.8 Hz, 1H).

[0956] The compounds of Examples 204 to 206 were synthesized accordingto the production methods of Examples 202 and 203.

Example 204

[0957]1-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-3-methoxy-2-propanol

[0958] (Yellow Oil)

[0959]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.07 (m, 2H), 0.32-0.44 (m, 2H),0.84-0.93 (m, 1H), 1.98 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.86-2.93(m, 1H), 2.96-3.06 (m, 2H), 3.35 (s, 3H), 3.36-3.51 (m, 3H), 3.67 (s,3H), 6.54 (dd, J=1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.08 (dd,J=6.8, 8.8 Hz, 1H), 7.40 (dd, J=1.3, 8.8 Hz, 1H).

Example 205

[0960](2S)-1-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-3-methoxypropan-2-ol

[0961] (Yellow Oil)

[0962]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.07 (m, 2H), 0.32-0.44 (m, 2H),0.84-0.93 (m, 1H), 1.98 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.86-2.93(m, 1H), 2.96-3.06 (m, 2H), 3.35 (s, 3H), 3.36-3.51 (m, 3H), 3.67 (s,3H), 6.54 (dd, J=1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.08 (dd,J=6.8, 8.8 Hz, 1H), 7.40 (dd, J=1.3, 8.8 Hz, 1H).

Example 206

[0963]4-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-2-butanol

[0964] (Light Yellow Oil)

[0965]¹H NMR (400 MHz, CDCl₃) δ −0.01-0.11 (m, 2H), 0.27-0.39 (m, 2H),0.72-0.83 (m, 1H), 1.17-1.21 (m, 3H), 1.47-1.68 (m, 2H), 1.99 (s, 3H),2.41 (s, 3H), 2.45 (s, 3H), 2.88-3.02 (m, 2H), 3.18-3.28 (m, 1H),3.61-3.75 (m, 1H), 3.68 (s, 3H), 4.02-4.12 (m, 1H), 6.54 (d, J=6.8 Hz,1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.09 (dd, J=6.8, 8.8 Hz, 1H), 7.50 (d,J=8.8 Hz, 1H).

Example 207

[0966]4-[3-[Di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3-methoxybenzonitrile

[0967] After dissolvingN-[7-(4-bromo-2-methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine(60 mg) in N,N-dimethylformamide (0.26 mL), zinc cyanide (31 mg) andtetrakis (triphenylphosphine)palladium (0) complex (23 mg) were added,the mixture was heated and stirred at 95° C. for 12 hours and thencooled to room temperature, and ethyl acetate was added. After filteringout the precipitated insoluble portion, extraction was performed withethyl acetate. The obtained organic layer was washed with water anddried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:n-hexane=1:8) to obtain the title compound(32 mg) as a yellow oil.

[0968]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.07 (m, 4H), 0.28-0.35 (m, 4H),0.78-0.87 (m, 2H), 2.46 (s, 3H), 2.95-3.02 (m, 4H), 3.80 (s, 3H), 6.62(dd, J=1.3, 6.8 Hz, 1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.25 (d, J=1.1Hz, 1H), 7.38 (dd, J=1.1, 7.7 Hz, 1H), 7.52 (dd, J=1.3, 8.8 Hz, 1H),7.67 (d, J=7.7 Hz, 1H).

[0969] The compounds of Examples 208 to 210 were synthesized accordingto the production method of Example 207.

Example 208

[0970]4-[3-[(Cyclopropylmethyl)(tetrahydro-3-furanylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3-methoxybenzonitrile

[0971] (Yellow Amorphous)

[0972]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.08 (m, 2H), 0.30-0.41 (m, 2H),0.78-0.88 (m, 1H), 1.60-1.70 (m, 1H), 1.87-1.98 (m, 1H), 2.16-2.29 (m,1H), 2.45 (s, 3H), 2.84-2.94 (m, 2H), 3.02-3.10 (m, 1H), 3.20-3.28 (m,1H), 3.59-3.87 (m, 4H), 3.81 (s, 3H), 6.64 (dd, J=1.9, 6.8 Hz, 1H), 7.07(dd, J=6.8, 8.8 Hz, 1H), 7.26 (d, J=1.1 Hz, 1H), 7.38 (dd, J=1.1, 7.8Hz, 1H), 7.45 (dd, J=1.9, 8.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H)

Example 209

[0973]4-[3-[Di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3-methoxy-5-methylbenzonitrile

[0974] (Light Yellow Crystals)

[0975]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.08 (m, 4H), 0.25-0.37 (m, 4H),0.78-0.91 (m, 2H), 2.06 (s, 3H), 2.41 (s, 3H), 2.94-3.06 (m, 4H), 3.72(s, 3H), 6.48 (d, J=6.8 Hz, 1H), 7.06 (dd, J=6.8, 8.8 Hz, 1H), 7.09 (s,1H), 7.25 (s, 1H), 7.52 (d, J=8.8 Hz, 1H).

Example 210

[0976]4-[3-[(Cyclopropylmethyl)(tetrahydro-3-furanylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3-methoxy-5-methylbenzonitrile

[0977] (Light Yellow Crystals)

[0978]¹H NMR (400 MHz, CDCl₃) δ −0.06-0.03 (m, 2H), 0.27-0.36 (m, 2H),0.78-0.88 (m, 1H), 1.58-1.70 (m, 1H), 1.88-1.98 (m, 1H), 2.06 (s, 3H),2.19-2.32 (m, 1H), 2.40 (s, 3H), 2.84-2.96 (m, 2H), 3.02-3.10 (m, 1H),3.21-3.29 (m, 1H), 3.58-3.86 (m, 4H), 3.72 (s, 3H), 6.49 (dd, J=1.3, 6.8Hz, 1H), 7.07 (dd, J=6.8, 8.8 Hz, 1H), 7.09 (s, 1H), 7.25 (s, 1H), 7.44(dd, J=1.3, 8.8 Hz, 1H)

Example 211

[0979]5-((Cyclopropylmethyl)[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminomethyl)-2-furonitrile

[0980] Zinc cyanide (31 mg) and tetrakis(triphenylphosphine)palladium(0) complex (52 mg) were added to a solution ofN-[(5-bromo-2-furyl)methyl]-N-cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine(122 mg) in a mixture of N,N-dimethylformamide (3 mL) andN-methyl-2-pyrrolidinone (3 mL), and the mixture was heated at 155° C.for 4 hours. The reaction mixture was cooled to room temperature, waterwas added, extraction was performed with ethyl acetate, the extract waswashed with saturated aqueous sodium hydrogencarbonate and brine anddried over magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was subjected to silica gel columnchromatography, and the title compound (23 mg) was obtained from then-hexane:ethyl acetate (1:4) fraction as a yellow oil.

[0981]¹H NMR (400 MHz, CDCl₃) δ 0.01-0.08 (m, 2H), 0.33-0.40 (m, 2H),0.80-0.93 (m, 1H), 2.43 (s, 3H), 2.45 (s, 3H), 3.00 (d, J=6.8 Hz, 2H),3.68 (s, 6H), 4.37 (s, 2H), 6.27 (d, J=3.7 Hz, 1H), 6.48 (s, 2H), 6.59(dd, J=1.5, 7.0 Hz, 1H), 6.95 (d, J=3.5 Hz, 1H), 7.05 (dd, J=7.0, 8.8Hz, 1H), 7.29 (dd, J=1.4, 8.9 Hz, 1H)

Example 212

[0982]N,N-Dicyclopropylmethyl-N-[7-[2-methoxy-6-methyl-4-(1,3-thiazol-2-yl)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0983] After dissolvingN-[7-(4-bromo-2-methoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine(45 mg) in toluene (0.60 mL), tributylstannylthiazole (52 mg) andtetrakis (triphenylphosphine)palladium (0) complex (9 mg) were added,the mixture was heated and stirred at 120° C. for 2 hours and thencooled to room temperature, and ethyl acetate was added. After filteringout the precipitated insoluble portion, the solvent was distilled offunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (ethyl acetate:n-hexane=1:5) to obtain the titlecompound (30 mg) as white crystals.

[0984]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.08 (m, 4H), 0.25-0.38 (m, 4H),0.80-0.92 (m, 2H), 2.10 (s, 3H), 2.43 (s, 3H), 2.95-3.07 (m, 4H), 3.79(s, 3H), 6.53 (d, J=6.8 Hz, 1H), 7.06 (dd, J=6.8, 8.8 Hz, 1H), 7.38 (d,J=3.2 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.49 (s, 1H), 7.52 (s, 1H), 7.91(d, J=3.2 Hz, 1H).

[0985] The compound of Example 213 was synthesized according to theproduction method of Example 212.

Example 213

[0986]N,N-Dicyclopropylmethyl-N-[7-[2-methoxy-6-methyl-4-(3-pyridyl)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[0987] (Light Yellow Solid)

[0988]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.08 (m, 4H), 0.28-0.38 (m, 4H),0.81-0.92 (m, 2H), 2.11 (s, 3H), 2.45 (s, 3H), 2.96-3.08 (m, 4H), 3.77(s, 3H), 6.55 (d, J=6.8 Hz, 1H), 7.04 (s, 1H), 7.07 (dd, J=6.8, 8.8 Hz,1H), 7.15 (s, 1H), 7.40 (dd, J=4.8, 8.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H),7.95 (d, J=8.0 Hz, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.92 (s, 1H).

Example 214

[0989]3-((Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminomethyl)-2-pyridinol

[0990] (White Crystals)

[0991] After dissolvingN-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(2-methoxy-3-pyridyl)methyl]amine(63 mg) in ethanol (1 mL), a 4 N hydrochloric acid/ethyl acetatesolution (1 mL) was added at room temperature and the mixture was heatedto reflux for 3 hours. Saturated aqueous sodium hydrogencarbonate wasadded to the reaction mixture for neutralization while cooling on ice,and extraction was performed with ethyl acetate. The obtained organiclayer was washed with water and dried over magnesium sulfate, and thesolvent was distilled off under reduced pressure. The obtained residuewas purified by silica gel column chromatography (ethyl acetate) toobtain the title compound (49 mg) as white crystals.

[0992]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.06 (m, 2H), 0.27-0.38 (m, 2H),0.84-0.97 (m, 1H), 1.97 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.91-3.03(m, 2H), 3.66 (s, 3H), 4.36 (s, 2H), 6.27 (dd, J=6.4, 6.4 Hz, 1H), 6.50(d, J=6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.05 (dd, J=6.8, 8.8 Hz,1H), 7.23 (d, J=6.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.85 (d, J=6.4 Hz,1H).

[0993] The compound of Example 215 was synthesized according to theproduction method of Example 214.

Example 215

[0994]3-((Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminomethyl)-2-pyrazinol

[0995] (Light Yellow Crystals)

[0996]¹H NMR (400 MHz, CDCl₃) δ 0.00-0.09 (m, 2H), 0.30-0.49 (m, 2H),0.78-0.91 (m, 1H), 1.97 (s, 3H), 2.40 (s, 3H), 2.47 (s, 3H), 2.94-3.03(m, 2H), 3.66 (s, 3H), 4.69 (s, 2H), 6.57 (dd, J=1.3, 6.8 Hz, 1H), 6.66(s, 1H), 6.74 (s, 1H), 7.14 (dd, J=6.8, 8.8 Hz, 1H), 7.55 (dd, J=1.3,8.8 Hz, 1H), 7.83 (br s, 2H).

Example 216

[0997] 2-[3-[Di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3,5-dimethylphenol

[0998] A 1 M boron tribromide/dichloromethane solution (0.42 mL) wasadded to a solution ofN,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine(35 mg) in dichloromethane (10 mL) at room temperature under a nitrogenatmosphere, and the mixture was stirred for 10 minutes. The reactionmixture was added to ice water, extraction was performed with ethylacetate, and the organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theobtained residue was subjected to silica gel column chromatography, andthe title compound (17 mg) was obtained from the n-hexane:ethyl acetate(6:1) fraction as white crystals.

[0999]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.02 (m, 4H), 0.24-0.30 (m, 4H),0.74-0.82 (m, 2H), 2.23 (s, 3H), 2.32 (s, 3H), 2.50 (s, 3H), 2.88-3.00(m, 4H), 6.64 (d, J=6.8 Hz, 1H), 6.76 (s, 1H), 7.09 (dd, J=6.8, 8.0 Hz,1H), 7.48 (d, J=8.8 Hz, 1H), 7.65 (s, 1H).

[1000] MS(ESI)m/z 408 MH⁺

Example 217

[1001]N,N-Dicyclopropylmethyl-N-[7-(2-ethoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1002] After adding ethanol (2 μL), triphenylphosphine (15 mg) anddiethyl azodicarboxylate (9 μL) to a solution of2-[3-[di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3,5-dimethylphenol(15 mg) in tetrahydrofuran (0.45 mL) under a nitrogen atmosphere, themixture was stirred at room temperature overnight. The reaction mixturewas added to water, extraction was performed with ethyl acetate, and theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained residuewas subjected to silica gel column chromatography, and the titlecompound (3.7 mg) was obtained from the n-hexane:ethyl acetate (9:1)fraction as a yellow oil.

[1003]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 4H), 0.26-0.32 (m, 4H),0.80-0.92 (m, 2H), 1.06 (t, J=6.8 Hz, 3H), 2.04 (s, 3H), 2.39 (s, 3H),2.45 (s, 3H), 3.02 (d, J=6.4 Hz, 4H), 3.84-4.04 (m, 2H), 6.51 (dd,J=0.8, 8.4 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.04 (dd, J=6.8, 8.8 Hz,1H), 7.47 (dd, J=0.8, 8.8 Hz, 1H).

[1004] The compounds of Examples 218 to 223 were synthesized accordingto the production method of Example 217.

Example 218

[1005]N,N-Dicyclopropylmethyl-N-[7-[2-(2-fluoroethoxy)-4,6-dimethylphenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1006] (Yellow Oil)

[1007]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 4H), 0.26-0.34 (m, 4H),0.82-0.92 (m, 2H), 2.04 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 3.02 (d,J=6.4 Hz, 4H), 3.94-4.50 (m, 4H), 6.53 (dd, J=0.8, 7.2 Hz, 1H), 6.70 (s,1H), 6.82 (s, 1H), 7.05 (dd, J=7.2, 8.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H).

Example 219

[1008]N-[7-[2-(Cyclopropylmethoxy)-4,6-dimethylphenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[1009] (Yellow Oil)

[1010]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.08 (m, 6H), 0.28-0.38 (m, 6H),0.86-0.96 (m, 3H), 2.07 (s, 3H), 2.42 (s, 3H), 2.48 (s, 3H), 3.05 (d,J=6.8 Hz, 4H), 3.71 (dd, J=6.4, 10.0 Hz, 1H), 3.81 (dd, J=6.4, 10.0 Hz,1H), 6.55 (dd, J=1.6, 6.8 Hz, 1H), 6.71 (s, 1H), 6.80 (s, 1H), 7.08 (dd,J=6.8, 8.8 Hz, 1H), 7.51 (dd, J=1.6, 8.8 Hz, 1H).

Example 220

[1011]N,N-Dicyclopropylmethyl-N-[7-[2-(2-methoxyethoxy)-4,6-dimethylphenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1012] (Yellow Oil)

[1013]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 4H), 0.26-0.34 (m, 4H),0.78-0.88 (m, 2H), 2.02 (s, 3H), 2.38 (s, 3H), 2.44 (s, 3H), 3.00 (d,J=7.2 Hz, 4H), 3.11 (s, 3H), 3.28-3.36 (m, 1H), 3.38-3.44 (m, 1H),3.90-3.96 (m, 1H), 3.44-4.10 (m, 1H), 6.50 (dd, J=1.2, 7.2 Hz, 1H), 6.69(s, 1H), 6.77 (s, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.45 (dd, J=1.2,8.8 Hz, 1H).

[1014] MS(ESI) m/z 466 MH⁺

Example 221

[1015]N,N-Dicyclopropylmethyl-N-[7-(2-isopropoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1016] (Yellow Oil)

[1017]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.02 (m, 4H), 0.26-0.34 (m, 4H),0.82-0.92 (m, 2H), 0.96 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.0 Hz, 3H), 2.04(s, 3H), 2.41 (s, 3H), 2.46 (s, 3H), 2.98-3.08 (m, 4H), 4.24-4.36 (m,1H), 6.51 (d, J=6.8 Hz, 1H), 6.71 (s, 1H), 6.77 (s, 1H), 7.05 (dd,J=7.2, 8.8 Hz, 1H), 7.47 (dd, J=1.2, 8.8 Hz, 1H).

[1018] MS(ESI) m/z 450 MH⁺

Example 222

[1019]2-[3-[Di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3,5-dimethylphenoxymethylcyanide

[1020] (Yellow Oil)

[1021]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 4H), 0.26-0.34 (m, 4H),0.80-0.92 (m, 2H), 2.02 (s, 3H), 2.43 (s, 3H), 2.44 (s, 3H), 3.01 (d,J=6.4 Hz, 4H), 4.57 (dd, J=16.0, 25.6 Hz, 2H), 6.50 (dd, J=1.6, 6.8 Hz,1H), 6.81 (s, 1H), 6.92 (s, 1H), 7.06 (dd, J=6.8, 8.8 Hz, 1H), 7.50 (dd,J=1.6, 8.8 Hz, 1H).

[1022] MS(ESI) m/z 447 MH⁺

Example 223

[1023]N,N-Dicyclopropylmethyl-N-[7-[2,4-dimethyl-6-(2-tetrahydro-1H-1-pyrrolylethoxy)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1024] (Yellow Oil)

[1025]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 4H), 0.24-0.34 (m, 4H),0.78-0.88 (m, 2H), 1.56-1.64 (m, 4H), 2.01 (s, 3H), 2.20-2.32 (m, 4H),2.37 (s, 3H), 2.42 (s, 3H), 2.42-2.58 (m, 2H), 2.94-3.04 (m, 4H),3.92-4.06 (m, 2H), 6.47 (dd, J=1.6, 7.2 Hz, 1H), 6.64 (s, 1H), 6.74 (s,1H), 7.00 (dd, J=7.2, 9.2 Hz, 1H), 7.44 (dd, J=1.6, 8.8 Hz, 1H).

[1026] MS(ESI) m/z 505 MH⁺

Example 224

[1027]N-Cyclopropyl-N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1028] After dissolvingN-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine(100 mg) in methanol (10 mL), ((1-ethoxycyclopropyl)oxy)trimethylsilane(60 μL), acetic acid (298 μL) and sodium cyanoborohydride (171 mg) wereadded and the mixture was heated to reflux for 6 hours. After coolingthe reaction mixture to room temperature, saturated aqueous sodiumhydrogencarbonate was added, extraction was performed with ethylacetate, and the organic layer was washed with brine. After drying theobtained organic layer over anhydrous magnesium sulfate and filteringit, the solvent was concentrated under reduced pressure, the residue waspurified by silica gel column chromatography, and the title compound (74mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as ayellow oil.

[1029]¹H NMR (400 MHz, CDCl₃) δ −0.01-0.04 (m, 2H), 0.26-0.36 (m, 2H),0.46-0.52 (m, 4H), 0.80-0.90 (m, 1H), 2.00 (s, 3H), 2.41 (s, 3H), 2.43(s, 3H), 2.88-2.94 (m, 1H), 2.98-3.06 (m, 2H), 3.69 (s, 3H), 6.50 (dd,J=1.6, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.02 (dd, J=6.8, 8.8 Hz,1H), 7.42 (dd, J=1.6, 8.8 Hz, 1H).

[1030] The compound of Example 225 was synthesized according to theproduction method of Example 224.

Example 225

[1031]N-Cyclopropyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

[1032] (Light Yellow Oil)

[1033]¹H NMR (400 MHz, CDCl₃) δ 0.42-0.57 (m, 4H), 1.55-1.64 (m, 1H),1.75-1.95 (m, 3H), 2.00 (s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 2.86-2.92(m, 1H), 3.06-3.13 (m, 1H), 3.42-3.48 (m, 1H), 3.64-3.71 (m, 4H),3.79-3.88 (m, 2H), 6.50 (dd, J=1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s,1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.40 (dd, J=1.6, 8.8 Hz, 1H).

Example 226

[1034]N3-Cyclopropylmethyl-N-3-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]nicotinamide

[1035] Triethylamine (0.038 mL) and chloronicotinic acid hydrochloride(20 mg) were added to a solution ofN-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine(33 mg) in dichloromethane (0.8 mL) while cooling on ice, and themixture was stirred at the same temperature for 1 hour. Saturatedaqueous sodium hydrogencarbonate was added while cooling on ice,extraction was performed with ethyl acetate, and the extract was washedwith brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate:n-hexane=3:2) to obtain the title compound(36 mg) as white crystals.

[1036]¹H NMR (400 MHz, CDCl₃) δ 0.08-0.33 (m, 2H), 0.37-0.54 (m, 2H),1.03-1.17 (m, 1H), 2.02 (s, 3H), 2.31 (s, 3H), 2.38 (s, 3H), 3.52-3.62(m, 1H), 3.67 (s, 3H), 3.87-3.97 (m, 1H), 6.57 (dd, J=1.3, 6.8 Hz, 1H),6.65 (s, 1H), 6.69 (s, 1H), 6.95 (dd, J=4.8, 8.0 Hz, 1H), 7.17 (dd,J=6.8, 8.8 Hz, 1H), 7.27 (dd, J=1.3, 8.8 Hz, 1H), 7.62 (d, J=8.0 Hz,1H), 8.31 (d, J=4.8 Hz, 1H), 8.56 (s, 1H).

[1037] The compound of Example 227 was synthesized according to theproduction method of Example 226.

Example 227

[1038]N1-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N1-(3-pyridylmethyl)-1-cyclopropanecarboxyamide

[1039] (White Amorphous Substance)

[1040]¹H NMR (400 MHz, CDCl₃) δ 0.61-0.71 (m, 2H), 1.01-1.11 (m, 2H),1.45-1.52 (m, 1H), 1.91 (s, 3H), 2.39 (s, 3H), 2.40 (s, 0.3H), 3.67 (s,3H), 4.57 (d, J=14.0 Hz, 1H), 5.25 (d, J=14.0 Hz, 1H), 6.58 (d, J=6.8Hz, 1H), 6.66 (s, 1H), 6.75 (s, 1H), 6.77 (d, J=8.8 Hz, 1H), 7.04 (dd,J=6.8, 8.8 Hz, 1H), 7.11 (dd, J=4.8, 8.0 Hz, 1H), 7.57 (d, J=8.0 Hz,1H), 8.30 (s, 1H), 8.41 (d, J=4.8 Hz, 1H)

Example 228

[1041]N,N-Dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfinyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1042] m-Chloroperbenzoic acid (234 mg) was added to a solution ofN,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine(200 mg) in dichloromethane (10 mL) at 0° C., and the mixture wasstirred for 2 hours. Water was added to the reaction mixture, extractionwas performed with ethyl acetate, the extract was washed with saturatedaqueous sodium hydrogencarbonate and brine and dried over magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was subjected to silica gel column chromatography (20 g), andthe title compound (162 mg) was obtained from the n-hexane:ethyl acetate(1:1) fraction as a light yellow oil.

[1043]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.08 (m, 4H), 0.28-0.38 (m, 4H),0.80-0.94 (m, 2H), 1.94 (s, 1.5H), 2.00 (s, 1.5H), 2.39 (s, 3H), 2.96(s, 1.5H), 2.97 (s, 1.5H), 3.04-3.16 (m, 4H), 3.64 (s, 1.5H), 3.66 (s,1.5H), 6.66 (s, 0.5H), 6.67 (s, 0.5H), 6.72 (dd, J=2.6, 6.9 Hz, 0.5H),6.73 (dd, J=2.6, 6.9 Hz, 0.5H), 6.74 (s, 0.5H), 6.76 (s, 0.5H), 7.15(dd, J=6.8, 8.9 Hz, 0.5H), 7.16 (dd, J=6.8, 8.9 Hz, 0.5H), 7.60-7.68 (m,1H)

Example 229

[1044]N,N-Dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfonyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1045] m-Chloroperbenzoic acid (91 mg) was added to a solution ofN,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfinyl)pyrazolo[1,5-a]pyridin-3-yl]amine(162 mg) in dichloromethane (10 mL) at 0° C., and the mixture wasstirred for 4 hours. Water was added to the reaction mixture, extractionwas performed with ethyl acetate, the extract was washed with saturatedaqueous sodium hydrogencarbonate and brine and dried over magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was subjected to silica gel column chromatography (10 g), andthe title compound (9 mg) was obtained from the n-hexane:ethyl acetate(1:2) fraction as a yellow oil.

[1046]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.08 (m, 4H), 0.24-0.34 (m, 4H),0.79-0.92 (m, 2H), 1.96 (s, 3H), 2.38 (s, 3H), 3.08 (dd, J=3.7, 6.8 Hz,4H), 3.21 (s, 3H), 3.64 (s, 3H), 6.66 (s, 1H), 6.75 (s, 1H), 6.78 (dd,J=1.4, 6.9 Hz, 1H), 7.19 (dd, J=6.9, 8.9 Hz, 1H), 7.72 (dd, J=1.4, 8.9Hz, 1H).

Example 230

[1047]N,N-Dicyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1048]2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitrosopyrazolo[1,5-a]pyridine(200 mg) was suspended in ethanol (10 mL), and then water (5 mL), aceticacid (0.5 mL) and zinc powder (200 mg) were added and the mixture washeated and stirred at 60° C. for 1 hour. The reaction mixture wasfiltered, water was added to the filtrate, extraction was performed withethyl acetate and the organic layer was washed with saturated aqueoussodium hydrogencarbonate and brine. The obtained organic layer was driedover anhydrous magnesium sulfate and filtered, and then the solvent wasconcentrated under reduced pressure to obtain2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridine-3-amineas a crude product. This was dissolved in tetrahydrofuran (5 mL) withoutpurification, and after adding cyclopropanecarboxyaldehyde (0.166 mL)and 3 M aqueous sulfuric acid (0.739 mL), sodium borohydride (56 mg) wasadded in five portions while vigorously stirring on ice, and stirringwas continued for 1 hour. Saturated aqueous sodium hydrogencarbonate wasadded to the reaction mixture, extraction was performed with ethylacetate, and the extract was washed with brine. After drying overanhydrous magnesium sulfate and filtration, the solvent was concentratedunder reduced pressure, the residue was purified by silica gel columnchromatography, and the title compound (240 mg) was obtained from then-hexane:ethyl acetate (30:1) fraction as a yellow oil.

[1049]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 4H), 0.26-0.34 (m, 4H),0.80-0.90 (m, 2H), 2.00 (m, 3H), 2.41 (s, 3H), 2.87-2.98 (m, 4H), 3.70(s, 3H), 3.86 (s, 3H), 6.44 (dd, J=1.6, 6.8 Hz, 1H), 6.69 (s, 1H), 6.77(s, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.39 (dd, J=1.6, 8.8 Hz, 1H).

[1050] The compounds of Examples 231 to 236 were synthesized accordingto the production method of Example 230.

Example 231

[1051]N-[2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-ditetrahydro-2H-4-pyranylamine

[1052] (Light Brown Powder)

[1053]¹H NMR (400 MHz, CDCl₃) δ 1.42-1.56 (m, 4H), 1.72-1.80 (m, 4H),1.99 (s, 3H), 3.33-3.43 (m, 6H), 3.70 (s, 3H), 3.83 (s, 3H), 3.90-3.96(m, 4H), 6.43 (dd, J=1.6, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.04(dd, J=6.8, 8.8 Hz, 1H), 7.26 (dd, J=1.6, 8.8 Hz, 1H).

Example 232

[1054]N,N-Dicyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]amine

[1055] (White Crystals)

[1056]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.05 (m, 4H), 0.27-0.34 (m, 4H),0.78-0.91 (m, 2H), 2.44 (s, 3H), 2.87-2.96 (m, 4H), 3.71 (s, 6H), 3.87(s, 3H), 6.47 (dd, J=1.3, 6.8 Hz, 1H), 6.50 (s, 2H), 7.01 (dd, J=6.8,8.8 Hz, 1H), 7.37 (dd, J=1.3, 8.8 Hz, 1H).

Example 233

[1057]N,N-Dicyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]amine

[1058] (Yellow Oil)

[1059]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.05 (m, 4H), 0.23-0.33 (m, 4H),0.79-0.91 (m, 2H), 2.02 (s, 3H), 2.85-2.99 (m, 4H), 3.68 (s, 3H), 3.86(s, 3H), 3.87 (s, 3H), 6.40 (dd, J=1.5, 6.8 Hz, 1H), 6.43 (d, J=2.2 Hz,1H), 6.47 (d, J=2.2 Hz, 1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.38 (dd,J=1.5, 8.8 Hz, 1H).

Example 234

[1060]N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[1061] (White Crystals)

[1062]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.06 (m, 4H), 0.24-0.35 (m, 4H),0.79-0.90 (m, 2H), 2.42 (s, 3H), 2.86-2.99 (m, 4H), 3.71 (s, 3H), 3.87(s, 3H), 6.46 (dd, J=1.3, 6.8 Hz, 1H), 6.74 (s, 1H), 6.97 (s, 1H), 7.03(dd, J=6.8, 8.8 Hz, 1H), 7.42 (dd, J=1.3, 8.8 Hz, 1H)

Example 235

[1063]N,N-Dicyclopropylmethyl-N-[2-methoxy-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1064] (Light Yellow Crystals)

[1065]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.02 (m, 4H), 0.25-0.31 (m, 4H),0.79-0.90 (m, 2H), 2.03 (s, 6H), 2.86-2.98 (m, 4H), 3.85 (s, 3H), 3.85(s, 3H), 6.33 (dd, J=1.5, 6.8 Hz, 1H), 6.70 (s, 2H), 7.01 (dd, J=6.8,8.8 Hz, 1H), 7.39 (dd, J=1.5, 8.8 Hz, 1H).

Example 236

[1066]N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

[1067] (Yellow Oil)

[1068]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.05 (m, 4H), 0.27-0.33 (m, 4H),0.78-0.89 (m, 2H), 2.86-2.97 (m, 4H), 3.88(s, 3H), 3.90 (s, 3H), 6.47(dd, J=1.5, 6.8 Hz, 1H), 6.92 (dd, J=2.6, 8.6 Hz, 1H), 7.01 (dd, J=6.8,8.8 Hz, 1H), 7.06 (d, J=2.6 Hz, 1H), 7.43 (dd, J=1.5, 8.8 Hz, 1H), 7.45(d, J=8.6 Hz, 1H).

Example 237

[1069] tert-ButylN-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]carbamate

[1070] After dissolving tert-butylN-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate (300 mg) in1,2-dimethoxyethane (10 mL) and water (5 mL),6-methyl-2,4-dimethoxyphenylboric acid (258 mg), tetrakis(triphenylphosphine)palladium (0) complex (203 mg) and barium hydroxideoctahydrate (415 mg) were added and the mixture was heated and stirredat 80° C. for 3 hours. Water was added to the reaction mixture,extraction was performed with ethyl acetate and the extract was washedwith brine. After drying the obtained organic layer over anhydrousmagnesium sulfate and filtering it, the solvent was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography, and the title compound (230 mg) was obtained from then-hexane:ethyl acetate (5:1) fraction as a brown oil.

[1071]¹H NMR (400 MHz, CDCl₃) δ 1.53 (s, 9H), 2.02 (s, 3H), 3.66 (s,3H), 3.87 (s, 3H), 3.90 (s, 3H), 6.42 (d, J=2.0 Hz, 1H), 6.47 (d, J=2.0Hz, 1H), 6.49 (dd, J=1.2, 6.8 Hz, 1H), 6.94 (dd, J=6.8, 8.8 Hz, 1H),7.26-7.33 (m, 1H).

Example 238

[1072]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

[1073] After dissolving tert-butylN-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]carbamate(50 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 15 mg) wasadded while cooling on ice, and then 2-tetrahydrofuranylmethyl chloride(16 μL) was added and the mixture was stirred for 3 hours at 60° C.under a nitrogen stream. Water was added to the reaction mixture,extraction was performed with ethyl acetate and the extract was washedwith brine. After drying over anhydrous magnesium sulfate andfiltration, the solvent was concentrated under reduced pressure toobtain tert-butylN-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylcarbamate.The crude product was dissolved in ethyl acetate (2 mL) withoutpurification, a 4 N hydrochloric acid/ethyl acetate solution (4 mL) wasadded, and the mixture was stirred at 40° C. for 1 hour. The reactionmixture was neutralized with 5 N aqueous sodium hydroxide while coolingon ice, and then extraction was performed with ethyl acetate and theorganic layer was washed with water and brine. The obtained organiclayer was dried over anhydrous magnesium sulfate and filtered, and thesolvent was concentrated under reduced pressure to obtainN-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamineas a crude product. This was dissolved in tetrahydrofuran (2 mL) withoutpurification, and after adding cyclopropanecarboxyaldehyde (27 μL) and 3M aqueous sulfuric acid (0.121 mL), sodium borohydride (9 mg) was addedin five portions while vigorously stirring on ice, and stirring wascontinued for 30 minutes. Saturated aqueous sodium hydrogencarbonate wasadded to the reaction mixture, extraction was performed with ethylacetate, the solvent was concentrated, the residue was purified bysilica gel column chromatography, and the title compound (31 mg) wasobtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.

[1074]¹H NMR (400 MHz, CDCl₃) δ −0.06-0.01 (m, 2H), 0.25-0.32 (m, 2H),0.80-0.90 (m, 1H), 1.52-1.70 (m, 1H), 1.74-1.95 (m, 3H), 2.01 (s, 1.5H),2.03 (s, 1.5H), 2.80-3.06 (m, 3H), 3.26-3.35 (m, 1H), 3.65-3.72 (m, 4H),3.80-3.90 (m, 8H), 6.38-6.42 (m, 1H), 6.44 (s, 1H), 6.47 (s, 1H),6.99-7.05 (m, 1H), 7.34-7.40 (m, 1H).

[1075] The compounds of Examples 239 to 255 below were synthesizedaccording to the production methods of Examples 237 and 238.

Example 239

[1076]N-Cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[1077] (Light Yellow Oil)

[1078]¹H NMR (400 MHz, CDCl₃) δ −0.08-0.04 (m, 2H), 0.22-0.36 (m, 2H),0.78-0.88 (m, 1H), 1.60-1.70 (m, 1H), 1.85-1.97 (m, 1H), 2.00 (s, 3H),2.21-2.31 (m, 1H), 2.41 (s, 3H), 2.75-2.89 (m, 2H), 2.92-3.03 (m, 1H),3.09-3.19 (m, 1H), 3.54-3.82 (m, 4H), 3.70 (s, 3H), 3.85 (s, 3H), 6.41(dd, J=1.5, 6.8 Hz, 1H), 6.59 (s, 1H), 6.76 (s, 1H), 7.03 (dd, J=6.8,8.8 Hz, 1H), 7.31 (dd, J=1.5, 8.8 Hz, 1H).

Example 240

[1079]N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine

[1080] (Yellow Oil)

[1081]¹H NMR (400 MHz, CDCl₃) δ −0.06-0.03 (m, 2H), 0.26-0.35 (m, 2H),0.78-0.87 (m, 1H), 1.57-1.68 (m, 1H), 1.85-1.97 (m, 1H), 2.20-2.31 (m,1H), 2.42 (s, 3H), 2.78-2.88 (m, 2H), 2.93-3.03 (m, 1H), 3.10-3.19 (m,1H), 3.56-3.84 (m, 4H), 3.71 (s, 3H), 3.86 (s, 3H), 6.47 (d, J=6.8 Hz,1H), 6.74 (s, 1H), 6.97 (s, 1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.34 (d,J=8.8 Hz, 1H)

Example 241

[1082]N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine

[1083] (Yellow Oil)

[1084]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.08 (m, 2H), 0.28-0.38 (m, 2H),0.75-0.87 (m, 1H), 1.58-1.69 (m, 1H), 1.84-1.95 (m, 1H), 2.16-2.29 (m,1H), 2.78-2.86 (m, 2H), 2.93-3.01 (m, 1H), 3.09-3.18 (m, 1H), 3.57-3.85(m, 4H), 3.88 (s, 3H), 3.89 (s, 3H), 6.48 (dd, J=1.3, 6.8 Hz, 1H), 6.92(dd, J=2.4, 8.8 Hz, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.06 (d, J=2.4Hz, 1H), 7.34 (dd, J=1.3, 8.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H)

Example 242

[1085]N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2-furanylmethylamine

[1086] (Yellow Oil)

[1087]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.04 (m, 2H), 0.27-0.34 (m, 2H),0.78-0.88 (m, 1H), 1.49-1.68 (m, 2H), 1.71-1.95 (m, 2H), 2.82-2.95 (m,2H), 2.98-3.05 (m, 1H), 3.27-3.35 (m, 1H), 3.53-3.72 (m, 1H), 3.78-3.88(m, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 6.48 (dd, J=1.3, 6.8 Hz, 1H), 6.91(dd, J=2.4, 8.4 Hz, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.06 (d, J=2.4Hz, 1H), 7.42 (dd, J=1.3, 8.8 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H)

Example 243

[1088]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[1089] (Light Yellow Oil)

[1090]¹H NMR (400 MHz, CDCl₃) δ −0.06-0.02 (m, 2H), 0.25-0.35 (m, 2H),0.77-0.86 (m, 1H), 1.55-1.70 (m, 1H), 1.86-1.96 (m, 1H), 2.02 (s, 1.5H),2.03 (s, 1.5H), 2.22-2.30 (m, 1H), 2.76-2.88 (m, 2H), 2.93-3.02 (m, 1H),3.10-3.18 (m, 1H), 3.55-3.62 (m, 1H), 3.63-3.68 (m, 1H), 3.68 (s, 1.5H),3.69 (s, 1.5H), 3.73-3.85 (m, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 6.41 (dd,J=1.2, 6.8 Hz, 1H), 6.43 (d, J=2.0 Hz, 1H), 6.47 (d, J=2.0 Hz, 1H), 7.02(dd, J=6.8, 8.8 Hz, 1H), 7.28-7.32 (m, 1H)

Example 244

[1091]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[1092] (Yellow Amorphous)

[1093]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.36 (m, 2H),0.78-0.90 (m, 1H), 1.58-1.70 (m, 1H), 1.85-1.96 (m, 1H), 2.20-2.33 (m,1H), 2.44 (s, 3H), 2.83 (d, J=6.8 Hz, 2H), 2.98 (dd, J=8.5, 12.0 Hz,1H), 3.14 (dd, J=6.7, 12.0 Hz, 1H), 3.59 (dd, J=5.9, 8.5 Hz, 1H),3.62-3.86 (m, 3H), 3.72 (s, 6H), 3.87 (s, 3H), 6.49 (dd, J=1.5, 6.7 Hz,1H), 6.51 (s, 2H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.30 (dd, J=1.5, 8.8Hz, 1H)

Example 245

[1094]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

[1095] (Yellow Crystals)

[1096]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.36 (m, 2H),0.80-0.93 (m, 1H), 1.60-1.72 (m, 1H), 1.73-1.96 (m, 3H), 2.45 (s, 3H),2.83-2.96 (m, 2H), 3.02 (dd, J=7.0, 12.0 Hz, 1H), 3.33 (dd, J=5.7, 12.0Hz, 1H), 3.64-3.76 (m, 1H), 3.72 (s, 6H), 3.80-3.92 (m, 2H), 3.87 (s,3H), 6.49 (dd, J=1.3, 6.8 Hz, 1H), 6.51 (s, 2H), 7.03 (dd, J=6.8, 8.9Hz, 1H), 7.37 (dd, J=1.5, 8.8 Hz, 1H).

Example 246

[1097]N-Cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

[1098] (Yellow Oil)

[1099]¹H NMR (400 MHz, CDCl₃) δ −0.08-0.03 (m, 2H), 0.22-0.33 (m, 2H),0.80-0.92 (m, 1H), 1.56-1.70 (m, 1H), 1.73-1.96 (m, 3H), 1.99 (s, 3H),2.40 (s, 3H), 2.80-3.06 (m, 3H), 3.25-3.37 (m, 1H), 3.63-3.72 (m, 1H),3.69 (s, 3H), 3.79-3.91 (m, 2H), 3.85 (s, 3H), 6.40 (dd, J=1.3, 6.8 Hz,1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.37 (dd,J=1.3, 8.8 Hz, 1H)

Example 247

[1100]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(3-furylmethyl)amine

[1101] (Yellow Crystals)

[1102]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.36 (m, 2H),0.80-0.92 (m, 1H), 2.45 (s, 3H), 2.87 (d, J=6.6 Hz, 2H), 3.71 (s, 6H),3.88 (s, 3H), 4.11 (s, 2H), 6.34-6.38 (m, 1H), 6.48 (dd, J=1.5, 6.9 Hz,1H), 6.50 (s, 2H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.22-7.32 (m, 3H).

Example 248

[1103]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(2-furylmethyl)amine

[1104] (Yellow Oil)

[1105]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.28-0.37 (m, 2H),0.80-0.94 (m, 1H), 2.43 (s, 3H), 2.93 (d, J=6.6 Hz, 2H), 3.70 (s, 6H),3.86 (s, 3H), 4.24 (s, 2H), 6.07 (d, J=3.1 Hz, 1H), 6.22 (dd, J=1.8, 3.1Hz, 1H), 6.46 (dd, J=1.3, 6.8 Hz, 1H), 6.49 (s, 2H), 6.98 (dd, J=6.8,8.8 Hz, 1H), 7.21 (dd, J=1.5, 8.8 Hz, 1H), 7.24-7.34 (m, 1H).

Example 249

[1106]N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2-furanylmethylamine

[1107] (Yellow Oil)

[1108]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.36 (m, 2H),0.82-0.92 (m, 1H), 1.60-1.72 (m, 2H), 1.78-1.98 (m, 2H), 2.45 (s, 3H),2.84-2.98 (m, 2H), 3.02-3.08 (m, 1H), 3.30-3.38 (m, 1H), 3.68-3.74 (m,1H), 3.74 (s, 3H), 3.82-3.92 (m, 2H), 3.88 (s, 3H), 6.49 (d, J=7.2 Hz,1H), 6.77 (s, 1H), 6.99 (s, 1H), 7.06 (dd, J=6.8, 8.8 Hz, 1H), 7.43 (dd,J=1.6, 9.2 Hz, 1H)

[1109] MS (ESI) m/z 456 MH⁺

Example 250

[1110]N-[2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

[1111] (Yellow Oil)

[1112]¹H NMR (400 MHz, CDCl₃) δ 0.89 (t, J=7.6 Hz, 3H), 1.32-1.42 (m,2H), 1.56-1.66 (m, 1H), 1.86-1.96 (m, 1H), 1.99 (s, 1.5H), 2.00 (s,1.5H), 2.18-2.28 (m, 1H), 2.41 (s, 3H), 2.88-2.96 (m, 3H), 3.05-3.12 (m,1H), 3.53-3.58 (m, 1H), 3.63-3.69 (m, 1H), 3.70 (s, 3H), 3.72-3.83 (m,2H), 3.85 (s, 3H), 6.41 (dd, J=1.6, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s,1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.25-7.28 (m, 1H).

Example 251

[1113]N-[2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylmethylamine

[1114] (Yellow Oil)

[1115]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.6 Hz, 3H), 1.35-1.44 (m,2H), 1.58-1.66 (m, 1H), 1.74-1.96 (m, 3H), 1.99 (s, 1.5H), 2.00 (s,1.5H), 2.41 (s, 3H), 2.94 (dd, J=6.8, 12.4 Hz, 1H), 2.99 (t, J=7.6 Hz,1H), 3.25 (ddd, J=4.0, 5.6, 12.4 Hz, 1H), 3.64-3.70 (m, 1H), 3.70 (s,3H), 3.80-3.85 (m, 2H), 3.85 (s, 3H), 6.40 (dd, J=1.2, 6.8 Hz, 1H), 6.68(s, 1H), 6.76 (s, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.34 (td, J=1.8,6.8 Hz, 1H).

Example 252

[1116]N-Cyclopropylmethyl-N-[2-methoxy-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[1117] (Yellow Oil)

[1118]¹H NMR (400 MHz, CDCl₃) δ −0.10-0.00 (m, 2H), 0.22-0.32 (m, 2H),0.76-0.86 (m, 1H), 1.58-1.69 (m, 1H), 1.86-1.97 (m, 1H), 2.02 (s, 3H),2.03 (s, 3H), 2.20-2.31 (m, 1H), 2.79-2.86 (m, 2H), 2.93-3.02 (m, 1H),3.10-3.19 (m, 1H), 3.55-3.61 (m, 1H), 3.63-3.71 (m, 1H), 3.72-3.85 (m,2H), 3.84 (s, 3H), 3.85 (s, 3H), 6.34 (dd, J=1.3, 6.8 Hz, 1H), 6.70 (s,2H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.32 (dd, J=1.3, 8.8 Hz, 1H).

Example 253

[1119]N-Cyclopropylmethyl-N-7-[2-(fluoromethoxy)-4,6-dimethylphenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-3-furanylmethylamine

[1120] (Yellow Oil)

[1121]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.06 (m, 2H), 0.24-0.36 (m, 2H),0.78-0.90 (m, 1H), 1.60-1.72 (m, 1H), 1.90-1.98 (m, 1H), 2.08 (br s,3H), 2.22-2.32 (m, 1H), 2.45 (s, 3H), 2.80-2.90 (m, 2H), 2.96-3.04 (m,1H), 3.14-3.20 (m, 1H), 3.58-3.86 (m, 4H), 3.86 (s, 3H), 5.38-5.66 (m,2H), 6.45 (dd, J=1.2, 6.8 Hz, 1H), 6.96 (s, 1H), 6.99 (s, 1H), 7.06 (dd,J=6.8, 8.8 Hz, 1H), 7.35 (dd, J=1.2, 8.8 Hz, 1H)

Example 254

[1122]N-Cyclopropyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)amine

[1123] (Yellow Oil)

[1124]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.32 (m, 2H),0.82-0.92 (m, 1H), 2.44 (s, 3H), 2.94 (d, J=6.8 Hz, 2H), 3.30 (d, J=4.4Hz, 2H), 3.70 (s, 6H), 3.82-3.86 (m, 2H), 3.87 (s, 3H), 3.92-3.98 (m,2H), 4.91 (t, J=4.4 Hz, 1H), 6.48 (dd, J=1.6, 6.8 Hz, 1H), 6.49 (s, 2H),7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.38 (dd, J=1.6, 8.8 Hz, 1H).

[1125] MS(ESI) m/z 454 MH⁺

Example 255

[1126]N-Cyclopropyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-[2-(1,3-dioxolan-2-yl)ethyl]amine

[1127] (Yellow Oil)

[1128]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.28-0.34 (m, 2H),0.82-0.92 (m, 1H), 1.74-1.82 (m, 2H), 2.44 (s, 3H), 2.87 (d, J=6.8 Hz,2H), 3.22 (t, J=7.2 Hz, 2H), 3.71 (s, 6H), 3.82-3.90 (m, 2H), 3.86 (s,3H), 3.92-4.00 (m, 2H), 4.97 (t, J=4.4 Hz, 1H), 6.47 (dd, J=1.6, 6.8 Hz,1H), 6.49 (s, 2H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.31 (dd, J=1.6, 8.8Hz, 1H)

[1129] MS(ESI) m/z 468 MH⁺

Example 256

[1130]N-Cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1131] After dissolvingN-cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine(134 mg) in tetrahydrofuran (10 mL), tetrahydro-2H-4-pyrancarbaldehyde(131 mg) and sodium triacetoxyborohydride (243 mg) were added, and themixture was stirred at room temperature for 1 hour. Saturated aqueoussodium hydrogencarbonate was added to the obtained reaction mixture,extraction was performed with ethyl acetate, and the extract was washedwith brine. After drying over anhydrous magnesium sulfate andfiltration, the solvent was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography, and the titlecompound (120 mg) was obtained from the n-hexane:ethyl acetate (4:1)fraction as a yellow amorphous.

[1132]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.12 (m, 2H), 0.30-0.44 (m, 2H),0.84-0.97 (m, 1H), 1.30-1.44 (m, 2H), 1.58-1.74 (m, 1H), 1.78-1.90 (m,2H), 2.08 (s, 3H), 2.49 (s, 3H), 2.82-2.96 (m, 2H), 2.97-3.10 (m, 2H),3.38 (dt, J=2.0, 12.0 Hz, 2H), 3.79 (s, 3H), 3.93 (s, 3H), 3.96-4.06 (m,2H), 6.49 (dd, J=1.3, 6.8 Hz, 1H), 6.77 (s, 1H), 6.85 (s, 1H), 7.10 (dd,J=6.8, 8.8 Hz, 1H), 7.39 (dd, J=1.3, 8.8 Hz, 1H).

[1133] The compounds of Examples 257 to 266 below were synthesizedaccording to the production method of Example 256.

Example 257

[1134]N-Cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[1135] (Yellow Oil)

[1136]¹H NMR (400 MHz, CDCl₃) δ −0.10-−0.01 (m, 2H), 0.20-0.28 (m, 2H),0.70-0.80 (m, 1H), 1.44-1.56 (m, 2H), 1.78-1.85 (m, 2H), 2.00 (s, 3H),2.41 (s. 3H), 2.87-2.99 (m, 2H), 3.14-3.34 (m, 2H), 3.34-3.42 (m, 2H),3.70 (s, 3H), 3.84 (s, 3H), 3.92-3.98 (m, 2H), 6.41 (dd, J=1.6, 6.8 Hz,1H), 6.69 (s, 1H), 6.76 (s, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.32 (dd,J=1.6, 8.8 Hz, 1H).

Example 258

[1137]N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylamine

[1138] (Yellow Oil)

[1139]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.04 (m, 2H), 0.21-0.30 (m, 2H),0.68-0.78 (m, 1H), 1.41-1.55 (m, 2H), 1.75-1.85 (m, 2H), 2.89-2.96 (m,2H), 3.12-3.22 (m, 1H), 3.32-3.42 (m, 2H), 3.88 (s, 3H), 3.89 (s, 3H),3.88-3.98 (m, 2H), 6.49 (dd, J=1.3, 6.8 Hz, 1H), 6.92 (dd, J=2.4, 8.8Hz, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.36 (dd,J=1.3, 8.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H).

Example 259

[1140]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[1141] (Yellow Oil)

[1142]¹H NMR (400 MHz, CDCl₃) δ −0.06-−0.02 (m, 2H), 0.20-0.28 (m, 2H),0.70-0.80 (m, 1H), 1.44-1.55 (m, 2H), 1.78-1.86 (m, 2H), 2.02 (s, 3H),2.88-3.00 (m, 2H), 3.14-3.24 (m, 1H), 3.34-3.42 (m, 2H), 3.69 (s, 3H),3.85 (s, 3H), 3.87 (s, 3H), 3.92-3.98 (m, 2H), 6.41 (dd, J=1.6, 6.8 Hz,1H), 6.44 (d, J=2.0 Hz, 1H), 6.47 (d, J=2.0 Hz, 1H), 7.03 (dd, J=6.8,8.8 Hz, 1H), 7.31 (dd, J=1.6, 8.8 Hz, 1H)

Example 260

[1143]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[1144] (Yellow Crystals)

[1145]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.06 (m, 2H), 0.24-0.33 (m, 2H),0.72-0.85 (m, 1H), 1.46-1.60 (m, 2H), 1.80-1.90 (m, 2H), 2.47 (s, 3H),2.97 (d, J=6.6 Hz, 2H), 3.16-3.28 (m, 1H), 3.41 (dt, J=1.8, 12.0 Hz,2H), 3.74 (s, 6H), 3.89 (s, 3H), 3.93-4.03 (m, 2H), 6.52 (dd, J=1.5, 7.0Hz, 1H), 6.54 (s, 2H), 7.06 (dd, J=6.8, 8.8 Hz, 1H), 7.34 (dd, J=1.3,8.9 Hz, 1H)

Example 261

[1146]N-Cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

[1147] (Yellow Oil)

[1148]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.06 (m, 2H), 0.26-0.38 (m, 2H),0.78-0.88 (m, 1H), 1.32-1.44 (m, 1H), 1.62-1.76 (m, 2H), 2.09 (s, 3H),2.09-2.16 (m, 1H), 2.50 (s, 3H), 2.94-3.08 (m, 2H), 3.20-3.30 (m, 3H),3.79 (s, 3H), 3.84-3.92 (m, 1H), 3.94 (s, 3H), 4.12-4.22 (m, 1H), 6.51(dd, J=1.2, 6.8 Hz, 1H), 6.78 (s, 1H), 6.85 (s, 1H), 7.13 (dd, J=6.8,8.8 Hz, 1H), 7.39 (dd, J=1.6, 9.2 Hz, 1H).

Example 262

[1149]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1150] (Yellow Crystals)

[1151]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.08 (m, 2H), 0.28-0.40 (m, 2H),0.80-0.94 (m, 1H), 1.20-1.38 (m, 2H), 1.52-1.70 (m, 1H), 1.74-1.84 (m,2H), 2.47 (s, 3H), 2.84 (d, J=6.6 Hz, 2H), 2.97 (d, J=6.9 Hz, 2H), 3.33(dt, J=2.0, 12.0 Hz, 2H), 3.75 (s, 6H), 3.89 (s, 3H), 3.90-4.00 (m, 2H),6.52 (dd, J=1.4, 6.9 Hz, 1H), 6.54 (s, 2H), 7.04 (dd, J=6.8, 8.8 Hz,1H), 7.33 (dd, J=1.4, 8.8 Hz, 1H)

Example 263

[1152]N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylamine

[1153] (Yellow Solid)

[1154]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.02 (m, 2H), 0.28-0.32 (m, 2H),0.74-0.84 (m, 1H), 1.50-1.64 (m, 2H), 1.84-1.92 (m, 2H), 2.47 (s, 3H),2.99 (br d, J=6.4 Hz, 2H), 3.20-3.30 (m, 1H), 3.40-3.48 (m, 2H), 3.77(s, 3H), 3.90 (s, 3H), 3.96-4.04 (m, 2H), 6.53 (dd, J=1.6, 8.8 Hz, 1H),6.79 (s, 1H), 7.02 (s, 1H), 7.09 (dd, J=6.8, 8.8 Hz, 1H), 7.41 (dd,J=1.2, 8.8 Hz, 1H)

[1155] MS(ESI) m/z 456 MH⁺

Example 264

[1156]N-Cyclopropylmethyl-N-[2-methoxy-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[1157] (Yellow Oil)

[1158]¹H NMR (400 MHz, CDCl₃) δ −0.10-−0.05 (m, 2H), 0.17-0.24 (m, 2H),0.67-0.78 (m, 1H), 1.42-1.55 (m, 2H), 1.77-1.87 (m, 2H), 2.02 (s, 6H),2.90-2.96 (m, 2H), 3.13-3.23 (m, 1H), 3.33-3.43 (m, 2H), 3.83 (s, 3H),3.85 (s, 3H), 3.90-3.99 (m, 2H), 6.35 (dd, J=1.3, 6.8 Hz, 1H), 6.70 (s,2H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.32 (dd, J=1.3, 8.8 Hz, 1H)

Example 265

[1159]N-[2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranyl-N-tetrahydro-2H-4-pyranylmethylamine

[1160] (White Amorphous)

[1161]¹H NMR (400 MHz, CDCl₃) δ 1.16-1.29 (m, 2H), 1.39-1.59 (m, 3H),1.64-1.84 (m, 4H), 1.99 (s, 3H), 2.41 (s, 3H), 2.90-3.04 (m, 3H),3.20-3.40 (m, 4H), 3.70 (s, 3H), 3.83 (s, 3H), 3.86-3.97 (m, 4H), 6.41(dd, J=1.3, 6.8 Hz, 1H), 6.68 (s, 1H), 6.75 (s, 1H), 7.02 (dd, J=6.8,8.8 Hz, 1H), 7.21 (dd, J=1.3, 8.8 Hz, 1H)

Example 266

[1162]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methbxypyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-oxazol-2-ylmethyl)amine

[1163] (Yellow Oil)

[1164]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.10 (m, 2H), 0.28-0.38 (m, 2H),0.82-0.96 (m, 1H), 2.43 (s, 3H), 2.97 (d, J=6.6 Hz, 2H), 3.69 (s, 6H),3.84 (s, 3H), 4.38 (s, 2H), 6.44-6.53 (m, 1H), 6.49 (s, 2H), 7.00 (s,1H), 7.01 (dd, J=6.7, 8.8 Hz, 1H), 7.27 (dd, J=1.5, 8.8 Hz, 1H), 7.55(s, 1H).

[1165] MS(ESI) m/z 449 MH⁺

Example 267

[1166]N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-pyridyl)amine

[1167] After dissolving[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine(40 mg) in toluene (1 mL), 2-bromopyridine (0.013 mL), sodium t-butoxide(25 mg) and dichlorobis(tri-o-tolylphosphine)palladium complex (3 mg)were added and the mixture was heated and stirred at 120° C. for 5hours. The mixture was cooled to room temperature, water was added, andextraction was performed with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography, and the title compound (12 mg) wasobtained from the ethyl acetate:n-hexane (1:2) fraction as whitecrystals.

[1168]¹H NMR (400 MHz, CDCl₃) δ 2.05 (s, 3H), 2.35 (s, 3H), 2.40 (s,3H), 3.70 (s, 3H), 6.61 (dd, J=1.3, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s,1H), 6.89 (ddd, J=0.8, 4.8, 7.2 Hz, 1H), 6.97 (dd, J=0.8, 8.4 Hz, 1H),7.06 (dd, J=6.8, 8.8 Hz, 1H), 7.14 (dd, J=1.3, 8.8 Hz, 1H), 7.54 (ddd,J=0.8, 7.2, 8.4 Hz, 1H), 8.31 (dd, J=0.8, 4.8 Hz, 1H).

Example 268

[1169]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-pyridyl)amine

[1170] The title compound (4 mg) was obtained as light yellow crystalsin the same manner as Example 267 usingN-cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine(50 mg), with Pd₂(dba)₃CHCl₃ as the catalyst, and also using2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and sodium t-butoxide.

[1171]¹H NMR (400 MHz, CDCl₃) δ 0.05-0.17 (m, 2H), 0.29-0.41 (m, 2H),1.09-1.20 (m, 1H), 2.04 (s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 3.72 (s,3H), 6.18 (d, J=8.4 Hz, 1H), 6.58 (dd, J=4.8, 7.2 Hz, 1H), 6.62 (dd,J=0.8, 6.8 Hz, 1H), 6.71 (s, 1H), 6.79 (s, 1H), 7.12 (dd, J=6.8, 8.8 Hz,1H), 7.23 (dd, J=0.8, 8.8 Hz, 1H), 7.29 (dd, J=7.2, 8.4 Hz, 1H), 8.22(d, J=4.8 Hz, 1H).

[1172] The compounds of Examples 269 and 270 were synthesized accordingto the production methods of Examples 267 and 268.

Example 269

[1173]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-(2-pyridyl)amine

[1174] (Light Yellow Crystals)

[1175]¹H NMR (400 MHz, CDCl₃) δ 0.90-0.96 (m, 3H), 1.60-1.75 (m, 2H),2.41 (s, 3H), 2.45 (s, 3H), 3.74 (s, 6H), 6.14 (d, J=8.8 Hz, 1H), 6.52(s, 2H), 6.55 (dd, J=4.8, 7.2 Hz, 1H), 6.69 (dd, J=1.3, 6.8 Hz, 1H),7.11 (dd, J=6.8, 8.8 Hz, 1H), 7.15 (dd, J=1.3, 8.8 Hz, 1H), 7.25 (dd,J=7.2, 8.8 Hz, 1H), 8.21 (d, J=4.8 Hz, 1H).

Example 270

[1176]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(2-pyridyl)amine

[1177] (Light Yellow Crystals)

[1178]¹H NMR (400 MHz, CDCl₃) δ 0.09-0.17 (m, 2H), 0.32-0.40 (m, 2H),1.09-1.21 (m, 1H), 2.45 (s, 3H), 3.74 (s, 6H), 3.87 (s, 6H), 6.28 (d,J=8.4 Hz, 1H), 6.52 (s, 2H), 6.53 (dd, J=5.0, 7.2 Hz, 1H), 6.61 (dd,J=1.3, 6.8 Hz, 1H), 7.08 (dd, J=6.8, 8.8 Hz, 1H), 7.12 (dd, J=1.3, 8.8Hz, 1H), 7.27 (dd, J=7.2, 8.4 Hz, 1H), 8.18 (d, J=5.0 Hz, 1H).

Example 271

[1179]3-(2,5-Diethyl-1H-1-pyrrolyl)-7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridine

[1180] After dissolving7-(2,6-dimethoxy-4-methylphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine(600 mg) in a mixture of ethanol (30 mL) and water (30 mL), acetic acid(3 mL) and zinc powder (600 mg) were added and the mixture was stirredat 60° C. for 2 hours. The ethanol of the obtained reaction mixture wasdistilled off under reduced pressure, and then saturated aqueous sodiumhydrogencarbonate and ethyl acetate were added to the residue andextraction was performed with ethyl acetate. The obtained organic layerswere combined, washed with water and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridine-3-amine(500 mg) as a crude product.

[1181] The obtained crude7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-amine(160 mg) was dissolved in toluene (50 mL), and then 3,6-octanedione (1g) and acetic acid (15 mL) were added and the mixture was heated toreflux for 4 hours. The toluene of the obtained reaction mixture wasdistilled off under reduced pressure, and then saturated aqueous sodiumhydrogencarbonate was added to the residue and extraction was performedwith ethyl acetate. The extracted organic layer was washed with waterand dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The obtained residue was subjectedto silica gel column chromatography, and the title compound (19 mg) wasobtained from the n-hexane:ethyl acetate (10:1) fraction as whitecrystals.

[1182]¹H NMR (400 MHz, CDCl₃) δ 1.07 (t, J=7.6 Hz, 3H), 1.08 (t, J=7.6Hz, 6H), 2.25 (q, J=7.6 Hz, 2H), 2.26 (q, J=7.6 Hz, 2H), 2.45 (s, 3H),2.55 (q, J=8.0 Hz, 2H), 3.73 (s, 6H), 5.99 (s, 2H), 6.54 (s, 2H), 6.73(dd. J=2.0, 6.4 Hz, 1H), 7.10-7.15 (m, 2H).

[1183] The compounds of Examples 272 to 276 were synthesized accordingto the production method of Example 25.

Example 272

[1184]N3-Cyclopropylmethyl-N3-tetrahydro-3-furanylmethyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

[1185] (Yellow Oil)

[1186]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.05 (m, 2H), 0.35-0.42 (m, 2H),0.80-0.90 (m, 1H), 1.25 (t, J=7.6 Hz, 3H), 1.55-1.70 (m, 1H), 1.85-1.95(m, 1H), 2.07 (s, 3H), 2.20-2.30 (m, 1H), 2.77 (q, J=7.6 Hz, 2H), 2.90(d, J=6.8 Hz, 2H), 3.06-3.11 (m, 1H), 3.14 (s, 6H), 3.17-3.25 (m, 2H),3.60-3.84 (m, 4H), 6.46 (s, 1H), 6.53 (dd, J=1.6, 6.8 Hz, 1H), 7.02 (dd,J=6.8, 8.8 Hz, 1H), 7.45 (dd, J=1.6, 9.2 Hz, 1H), 8.16 (s, 1H).

Example 273

[1187]N3-Cyclopropylmethyl-N-3-tetrahydro-3-furanylmethyl-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

[1188] (Yellow Oil)

[1189]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.00 (m, 2H), 0.30-0.40 (m, 2H),0.75-0.90 (m, 1H), 1.21 (t, J=7.2 Hz, 3H), 1.60-1.70 (m, 1H), 1.85-1.97(m, 4H), 2.14 (s, 3H), 2.22-2.32 (m, 1H), 2.75 (q, J=7.6 Hz, 2H), 2.91(d, J=6.4 Hz, 2H), 3.05-3.15 (m, 7H), 3.20-3.28 (m, 1H), 3.59-3.88 (m,4H), 6.31 (s, 2H), 6.46 (dd, J=1.6, 6.8 Hz, 1H), 7.00 (dd. J=6.8, 9.2Hz, 1H), 7.43 (dd, J=1.2, 8.8 Hz, 1H).

Example 274

[1190]N-Cyclopropylmethyl-N-(1,3-dioxolan-2-ylmethyl)-N-[2-ethyl-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1191] (Yellow Oil)

[1192]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.04 (m, 2H), 0.34-0.38 (m, 2H),0.84-0.96 (m, 1H), 1.25 (t, J=7.6 Hz, 3H), 2.05 (s, 6H), 2.81 (q, J=7.6Hz, 2H), 3.07 (d, J=6.8 Hz, 2H), 3.41 (d, J=4.4 Hz, 2H), 3.86-3.90 (m,2H), 3.87 (s, 3H), 3.98-4.04 (m, 2H), 6.47 (dd, J=1.2, 6.8 Hz, 1H), 6.73(s, 2H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.51 (dd, J=1.2, 8.8 Hz, 1H).

Example 275

[1193]N3-Cyclopropylmethyl-N-3-(1,3-dioxolan-2-ylmethyl)-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

[1194] (Yellow Oil)

[1195]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.32-0.38 (m, 2H),0.80-0.92 (m, 1H), 1.28 (t, J=7.6 Hz, 3H), 2.08 (s, 3H), 2.81 (q, J=7.6Hz, 2H), 3.03 (d, J=6.8 Hz, 2H), 3.15 (s, 6H), 3.36 (d, J=4.4 Hz, 2H),3.80-3.88 (m, 2H), 3.92-4.00 (m, 2H), 4.91 (t, J=4.4 Hz, 1H), 6.46 (s,1H), 6.53 (dd, J=1.6, 6.8 Hz, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.49(dd, J=1.6, 8.8 Hz, 1H), 8.16 (s, 1H).

Example 276

[1196]N3-Cyclopropylmethyl-N-3-(1,3-dioxolan-2-ylmethyl)-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

[1197] (Yellow Oil)

[1198]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.32-0.38 (m, 2H),0.82-0.92 (m, 1H), 1.26 (t, J=7.6 Hz, 3H), 1.99 (s, 3H), 2.18 (s, 3H),2.81 (q, J=7.6 Hz, 2H), 3.07 (d, J=6.8 Hz, 2H), 3.16 (s, 6H), 3.04 (d,J=4.4 Hz, 2H), 3.82-3.90 (m, 2H), 3.96-4.02 (m, 2H), 4.96 (t, J=4.4 Hz,1H), 6.34 (s, 1H), 6.48 (dd, J=1.2, 6.8 Hz, 1H), 7.03 (dd, J=6.8, 8.8Hz, 1H), 7.50 (dd, J=1.2, 8.8 Hz, 1H).

[1199] The compounds of Examples 277 to 286 were synthesized accordingto the production method of Example 47.

Example 277

[1200]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylmethylamine

[1201] (Yellow Oil)

[1202]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.3 Hz, 3H), 1.20 (t, J=7.6Hz, 3H), 1.22-1.32 (m, 2H), 1.39 (ddq, J=7.3, 7.3, 7.3 Hz, 2H),1.51-1.63 (m, 1H), 1.70-1.78 (m, 2H), 2.43 (s, 3H), 2.74 (q, J=7.6 Hz,2H), 2.93-2.98 (m, 2H), 2.97 (dd, J=7.3, 7.3 Hz, 2H), 3.26-3.35 (m, 2H),3.70 (s, 6H), 3.90-3.97 (m, 2H), 6.51 (s, 2H), 6.59 (dd, J=1.3, 6.8 Hz,1H), 7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.41 (dd, J=1.3, 8.8 Hz, 1H).

Example 278

[1203]N-Butyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1204] (Yellow Oil)

[1205]¹H NMR (400 MHz, CDCl₃) δ 0.86 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.6Hz, 3H), 1.16-1.42 (m, 6H), 1.49-1.63 (m, 1H), 1.66-1.80 (m, 2H), 2.43(s, 3H), 2.73 (q, J=7.6 Hz, 2H), 2.95 (d, J=7.0 Hz, 2H), 3.00 (t, J=7.1Hz, 2H), 3.30 (dt, J=2.0, 12.0 Hz, 2H), 3.70 (s, 6H), 3.88-4.00 (m, 2H),6.51 (s, 2H), 6.59 (dd, J=1.4, 6.9 Hz, 1H), 7.00 (dd, J=6.8, 8.8 Hz,1H), 7.41 (dd, J=1.4, 8.8 Hz, 1H).

[1206] MS(ESI) m/z 466 MH⁺

Example 279

[1207]N-Cyclobutylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1208] (Yellow Oil)

[1209]¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J=7.6 Hz, 3H), 1.17-1.32 (m,2H), 1.50-1.66 (m, 3H), 1.67-1.94 (m, 6H), 2.25-2.40 (m, 1H), 2.43 (s,3H), 2.72 (q, J=7.5 Hz, 2H), 2.93 (d, J=7.0 Hz, 2H), 3.04 (d, J=7.1 Hz,2H), 3.31 (dt, J=1.9, 12.0 Hz, 2H), 3.69 (s, 6H), 3.88-4.00 (m, 2H),6.51 (s, 2H), 6.59 (dd, J=1.3, 6.8 Hz, 1H), 7.00 (dd, J=7.0, 8.8 Hz,1H), 7.39 (dd, J=1.5, 8.8 Hz, 1H).

[1210] MS(ESI) m/z 478 MH⁺

Example 280

[1211]N-Butyl-N-[2-ethyl-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1212] (Light Yellow Crystals)

[1213]¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.8 Hz, 3H), 1.21 (t, J=7.6Hz, 3H), 1.22-1.40 (m, 6H), 1.50-1.60 (m, 1H), 1.70-1.77 (m, 2H), 2.73(q, J=7.6 Hz, 2H), 2.95 (d, J=6.8 Hz, 2H), 3.00 (t, J=6.8 Hz, 2H),3.26-3.34 (m, 2H), 3.70 (s, 6H), 3.88 (s, 3H), 3.90-3.96 (m, 2H), 6.24(s, 2H), 6.58 (dd, J=1.6, 6.8 Hz, 1H), 6.99 (dd, J=6.8, 8.8 Hz, 1H),7.39 (dd, J=1.6, 8.8 Hz, 1H).

Example 281

[1214]N-Cyclobutylmethyl-N-[2-ethyl-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1215] (Light Yellow Crystals)

[1216]¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J=7.6 Hz, 3H), 1.23-1.30 (m,2H), 1.52-1.62 (m, 3H), 1.71-1.82 (m, 4H), 1.82-1.92 (m, 2H), 2.27-2.36(m, 1H), 2.72 (q, J=7.6 Hz, 2H), 2.93 (d, J=6.8 Hz, 2H), 3.03 (d, J=7.2Hz, 2H), 3.26-3.34 (m, 2H), 3.69 (s, 6H), 3.88 (s, 3H), 3.90-3.96 (m,2H), 6.24 (s, 2H), 6.57 (dd, J=1.2, 6.8 Hz, 1H), 6.99 (dd, J=6.8, 8.8Hz, 1H), 7.37 (dd, J=1.2, 8.8 Hz, 1H).

Example 282

[1217]N-Cyclopropylmethyl-N-[2-ethyl-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1218] (Light Yellow Crystals)

[1219]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.03 (m, 2H), 0.34-0.40 (m, 2H),0.80-0.90 (m, 1H), 1.23 (t, J=7.6 Hz, 3H), 1.23-1.34 (m, 2H), 1.54-1.64(m, 1H), 1.73-1.80 (m, 2H), 2.78 (q, J=7.6 Hz, 2H), 2.89 (d, J=6.8 Hz,2H), 3.05 (d, J=6.8 Hz, 2H), 3.27-3.36 (m, 2H), 3.71 (s, 6H), 3.89 (s,3H), 3.92-3.97 (m, 2H), 6.26 (s, 2H), 6.59 (dd, J=1.6, 6.8 Hz, 1H), 7.00(dd, J=6.8, 8.8 Hz, 1H), 7.43 (dd, J=1.6, 8.8 Hz, 1H)

Example 283

[1220]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-ditetrahydro-2H-4-pyranylmethylamine

[1221] (Yellow Amorphous)

[1222]¹H NMR (400 MHz, CDCl₃) δ 1.21 (t, J=7.6 Hz, 3H), 1.20-1.31 (m,4H), 1.52-1.60 (m, 2H), 1.70-1.78 (m, 4H), 2.44 (s, 3H), 2.74 (q, J=7.6Hz, 2H), 2.93 (d, J=6.8 Hz, 4H), 3.26-3.34 (m, 4H), 3.71 (s, 6H),3.90-3.96 (m, 4H), 6.52 (s, 2H), 6.62 (dd, J=1.6, 6.8 Hz, 1H), 7.02 (dd,J=6.8, 8.8 Hz, 1H), 7.41 (dd, J=1.6, 8.8 Hz, 1H).

Example 284

[1223]N3-Cyclopropylmethyl-N-3-tetrahydro-2H-4-pyranylmethyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

[1224] (Yellow Oil)

[1225]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.33-0.41 (m, 2H),0.78-0.91 (m, 1H), 1.28 (t, J=7.5 Hz, 3H), 1.23-1.36 (m, 2H), 1.54-1.67(m, 1H), 1.72-1.82 (m, 2H), 2.10 (s, 3H), 2.80 (q, J=7.5 Hz, 2H), 2.90(d, J=6.8 Hz, 2H), 3.07 (d, J=7.1 Hz, 2H), 3.17 (s, 6H), 3.33 (dt,J=2.0, 12.0 Hz, 2H), 3.92-4.00 (m, 2H), 6.48 (s, 1H), 6.55 (dd, J=1.5,6.8 Hz, 1H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.48 (dd, J=1.4, 8.8 Hz, 1H),8.19 (s, 1H).

Example 285

[1226]N3-Cyclopropylmethyl-N3-tetrahydro-2H-4-pyranylmethyl-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

[1227] (Yellow Oil)

[1228]¹H NMR (400 MHz, CDCl₃) δ −0.08-−0.02 (m, 2H), 0.29-0.35 (m, 2H),0.76-0.87 (m, 1H), 1.21 (t, J=7.6 Hz, 3H), 1.22-1.34 (m, 2H), 1.54-1.66(m, 1H), 1.72-1.81 (m, 2H), 1.96 (s, 3H), 2.15 (s, 3H), 2.75 (q, J=7.6Hz, 2H), 2.84-2.90 (m, 2H), 3.02-3.07 (m, 2H), 3.12 (s, 6H), 3.27-3.36(m, 2H), 3.90-3.98 (m, 2H), 6.30 (s, 1H), 6.44 (dd, J=1.3, 6.8 Hz, 1H),6.98 (dd, J=6.8, 8.8 Hz, 1H), 7.43 (dd, J=1.3, 8.8 Hz, 1H)

Example 286

[1229]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1230] (Yellow Oil)

[1231]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.00 (m, 2H), 0.31-0.36 (m, 2H),0.77-0.87 (m, 1H), 1.21 (t, J=7.6 Hz, 3H), 1.22-1.32 (m, 2H), 1.56-1.64(m, 1H), 1.72-1.80 (m, 2H), 2.00 (s, 3H), 2.72-2.79 (m, 2H), 2.87 (d,J=6.4 Hz, 2H), 3.04 (d, J=6.8 Hz, 2H), 3.27-3.35 (m, 2H), 3.67 (s, 3H),3.85 (s, 3H), 3.90-3.96 (m, 2H), 6.43 (d, J=2.0 Hz, 1H), 6.47 (d, J=2.0Hz, 1H), 6.49 (dd, J=1.2, 6.8 Hz, 1H), 6.99 (dd, J=6.8, 8.8 Hz, 1H),7.43 (dd, J=1.2, 8.8 Hz, 1H).

[1232] The compounds of Examples 287 to 292 were synthesized accordingto the production methods of Examples 102 and 103.

Example 287

[1233]N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(3-methyl-5-isoxazolyl)methyl]amine

[1234] (Light Yellow Oil)

[1235]¹H NMR (400 MHz, CDCl₃) δ −0.01-0.06 (m, 2H), 0.31-0.38 (m, 2H),0.82-0.92 (m, 1H), 1.96 (s, 3H), 2.22 (s, 3H), 2.39 (s, 3H), 2.44 (s,3H), 2.97-3.03 (m, 2H), 3.66 (s, 3H), 4.43 (s, 2H), 5.95 (s, 1H), 6.49(dd, J=1.3, 6.8 Hz, 1H), 6.65 (s, 1H), 6.73 (s, 1H), 7.03 (dd, J=6.8,8.8 Hz, 1H), 7.32 (dd, J=1.3, 8.8 Hz, 1H)

Example 288

[1236]N3-Cyclopropylmethyl-N-3-[6-(dimethylamino)-2-pyridyl]methyl-7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

[1237] (Yellow Oil)

[1238]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.02 (m, 2H), 0.25-0.32 (m, 2H),0.84-0.93 (m, 1H), 1.97 (s, 3H), 2.39 (s, 3H), 2.45 (s, 3H), 2.94-3.00(m, 2H), 3.04 (s, 6H), 3.66 (s, 3H), 4.37 (s, 2H), 6.34 (d, J=8.2 Hz,1H), 6.47 (dd, J=1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 6.99 (d,J=7.3 Hz, 1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.42 (dd, J=7.3, 8.2 Hz,1H), 7.47 (dd, J=1.3, 8.8 Hz, 1H)

Example 289

[1239]N-Cyclopropylmethyl-N-(5-isoxazolylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1240] (Light Yellow Oil)

[1241]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.08 (m, 2H), 0.31-0.41 (m, 2H),0.83-0.93 (m, 1H), 1.96 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.98-3.08(m, 2H), 3.66 (s, 3H), 4.52 (s, 2H), 6.14 (d, J=1.2 Hz, 1H), 6.51 (dd,J=1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.75 (s, 1H), 7.04 (dd, J=6.8, 8.8 Hz,1H), 7.31 (dd, J=1.3, 8.8 Hz, 1H), 8.10 (d, J=1.2 Hz, 1H).

Example 290

[1242]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)-N-propylamine

[1243] (Light Yellow Crystals)

[1244]¹H NMR (400 MHz, CDCl₃) δ 0.87 (t, J=7.2 Hz, 3H), 1.40 (tq, J=7.2,7.2 Hz, 2H), 2.44 (s, 3H), 2.44 (s, 3H), 3.14 (t, J=7.2 Hz, 2H), 3.29(d, J=4.4 Hz, 2H), 3.81 (s, 6H), 3.82-3.88 (m, 2H), 3.92-4.00 (m, 2H),4.92 (t, J=4.4 Hz, 1H), 6.48 (s, 2H), 6.57 (dd, J=1.6, 6.8 Hz, 1H), 7.04(dd, J=6.8, 8.8 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H)

Example 291

[1245]N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)amine

[1246] (Light Yellow Oil)

[1247]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.06 (m, 2H), 0.28-0.34 (m, 2H),0.82-0.92 (m, 1H), 2.42 (s, 3H), 2.44 (s, 3H), 3.02 (d, J=6.4 Hz, 2H),3.36 (d, J=4.4 Hz, 2H), 3.67 (s, 6H), 3.78-3.84 (m, 2H), 3.90-3.98 (m,2H), 4.92 (t, J=4.4 Hz, 1H), 6.47 (s, 2H), 6.56 (dd, J=1.2, 6.8 Hz, 1H),7.02 (dd, J=7.2, 8.8 Hz, 1H), 7.43 (dd, J=1.2, 8.8 Hz, 1H).

Example 292

[1248]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)-N-tetrahydro-3-furanylmethylamine

[1249] (Yellow Oil)

[1250]¹H NMR (400 MHz, CDCl₃) δ 1.56-1.66 (m, 1H), 1.86-1.96 (m, 1H),2.20-2.32 (m, 1H), 2.44 (s, 3H), 2.44 (s, 3H), 3.08-3.16 (m, 1H),3.22-3.32 (m, 3H), 3.56-3.68 (m, 2H), 3.69 (s, 6H), 3.72-3.84 (m, 2H),3.84-3.88 (m, 2H), 3.94-3.98 (m, 2H), 4.93 (t, J=4.4 Hz, 1H), 6.48 (s,2H), 6.59 (dd, J=1.2, 6.8 Hz, 1H), 7.06 (dd, J=7.2, 8.8 Hz, 1H), 7.39(dd, J=1.6, 8.8 Hz, 1H).

[1251] The compounds of Examples 293 and 294 were synthesized accordingto the production method of Example 159.

Example 293

[1252]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)-N-tetrahydro-2H-4-pyranylmethylamine

[1253] (Yellow Oil)

[1254]¹H NMR (400 MHz, CDCl₃) δ 1.22-1.32 (m, 2H), 1.50-1.60 (m, 1H),1.76-1.84 (m, 2H), 2.44 (s, 3H), 2.44 (s, 3H), 3.09 (d, J=6.8 Hz, 2H),3.25 (d, J=4.4 Hz, 2H), 3.24-3.36 (m, 2H), 3.70 (s, 6H), 3.82-3.88 (m,2H), 3.90-3.98 (m, 4H), 4.92 (t, J=4.4 Hz, 1H), 6.49 (s, 2H), 6.59 (dd,J=1.2, 6.8 Hz, 1H), 7.05 (dd, J=6.8, 8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H)

Example 294

[1255]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-ditetrahydro-2H-4-pyranylmethylamine

[1256] (Light Yellow Amorphous)

[1257]¹H NMR (400 MHz, CDCl₃) δ 1.21-1.32 (m, 4H), 1.48-1.61 (m, 2H),1.74-1.83 (m, 4H), 2.43 (s, 3H), 2.44 (s, 3H), 2.89-2.95 (m, 4H),3.26-3.35 (m, 4H), 3.70 (s, 6H), 3.89-3.96 (m, 4H), 6.48 (s, 2H), 6.59(dd, J=1.3, 6.8 Hz, 1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.31 (dd, J=1.3,8.8 Hz, 1H).

[1258] The compounds of Examples 295 to 298 were synthesized accordingto the production methods of Examples 237 and 238.

Example 295

[1259]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)-N-tetrahydro-3-furanylmethylamine

[1260] (Yellow Oil)

[1261]¹H NMR (400 MHz, CDCl₃) δ 1.54-1.66 (m, 1H), 1.86-1.96 (m, 1H),2.18-2.32 (m, 1H), 2.44 (s, 3H), 2.98-3.06 (m, 1H), 3.14-3.24 (m, 3H),3.52-3.68 (m, 2H), 3.71 (s, 6H), 3.72-3.84 (m, 2H), 3.86 (s, 3H),3.90-3.98 (m, 2H), 4.91 (t, J=4.4 Hz, 1H), 6.48 (dd, J=1.2, 6.8 Hz, 1H),6.49 (s, 2H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.30 (dd, J=1.2, 8.8 Hz,1H).

Example 296

[1262]N3-Cyclopropylmethyl-N-3-tetrahydro-3-furanylmethyl-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-methoxypyrazolo[1,5-a]pyridin-3-amine

[1263] (Yellow Oil)

[1264]¹H NMR (400 MHz, CDCl₃) δ −0.09-0.01 (m, 2H), 0.23-0.33 (m, 2H),0.75-0.86 (m, 1H), 1.58-1.69 (m, 1H), 1.86-1.96 (m, 1H), 1.97 (s, 3H),2.15 (s, 3H), 2.20-2.30 (m, 1H), 2.79-2.85 (m, 2H), 2.94-3.01 (m, 1H),3.10-3.18 (m, 1H), 3.13 (s, 6H), 3.55-3.61 (m, 1H), 3.63-3.70 (m, 1H),3.71-3.83 (m, 2H), 3.84 (s, 3H), 6.29 (s, 1H), 6.34 (dd, J=1.3, 6.8 Hz,1H), 6.99 (dd, J=6.8, 8.8 Hz, 1H), 7.29 (dd, J=1.3, 8.8 Hz, 1H)

Example 297

[1265]N3-Cyclopropylmethyl-N-3-tetrahydro-3-furanylmethyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-methoxypyrazolo[1,5-a]pyridin-3-amine

[1266] (Yellow Oil)

[1267]¹H NMR (400 MHz, CDCl₃) δ −0.06-0.05 (m, 2H), 0.25-0.36 (m, 2H),0.75-0.87 (m, 1H), 1.57-1.68 (m, 1H), 1.84-1.96 (m, 1H), 2.11 (s, 3H),2.15-2.29 (m, 1H), 2.78-2.85 (m, 2H), 2.92-3.01 (m, 1H), 3.08-3.17 (m,1H), 3.15 (s, 6H), 3.56-3.69 (m, 2H), 3.70-3.83 (m, 2H), 3.89 (s, 3H),6.41 (dd, J=1.3, 6.8 Hz, 1H), 6.44 (s, 1H), 7.01 (dd, J=6.8, 8.8 Hz,1H), 7.31 (dd, J=1.3, 8.8 Hz, 1H), 8.13 (s, 1H)

Example 298

[1268]N-Cyclopropylmethyl-N-(1,3-dioxolan-2-ylmethyl)-N-[2-methoxy-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

[1269] (Yellow Oil)

[1270]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.06 (m, 2H), 0.24-0.34 (m, 2H),0.84-0.96 (m, 1H), 2.07 (s, 6H), 2.99 (d, J=6.8 Hz, 2H), 3.35 (d, J=4.4Hz, 2H), 3.84-3.92 (m, 2H), 3.89 (s, 6H), 3.94-4.04 (m, 2H), 4.98 (t,J=4.4 Hz, 1H), 6.39 (d, J=6.8 Hz, 1H), 6.74 (s, 2H), 7.07 (dd, J=6.8,8.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H).

[1271] The compounds of Examples 299 to 312 were synthesized accordingto the production method of Example 256.

Example 299

[1272]N-Butyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1273] (Yellow Oil)

[1274]¹H NMR (400 MHz, CDCl₃) δ 0.83-0.89 (m, 3H), 1.18-1.38 (m, 6H),1.55-1.60 (m, 1H), 1.68-1.77 (m, 2H), 2.44 (s, 3H), 2.86 (d, J=6.8 Hz,2H), 2.90-2.95 (m, 2H), 3.25-3.32 (m, 2H), 3.71 (s, 6H), 3.85 (s, 3H),3.88-3.96 (m, 2H), 6.46-6.49 (m, 1H), 6.49 (s, 2H), 7.00 (dd, J=6.4, 8.8Hz, 1H), 7.22-7.24 (m, 1H).

Example 300

[1275]N-Cyclobutylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1276] (Light Yellow Crystals)

[1277]¹H NMR (400 MHz, CDCl₃) δ 1.18-1.30 (m, 2H), 1.50-1.62 (m, 3H),1.70-1.90 (m, 6H), 2.28-2.36 (m, 1H), 2.43 (s, 3H), 2.84 (d, J=7.2 Hz,2H), 2.95 (d, J=7.2 Hz, 2H), 3.25-3.33 (m, 2H), 3.70 (s, 6H), 3.85 (s,3H), 3.88-3.94 (m, 2H), 6.47 (dd, J=1.2, 6.8 Hz, 1H), 6.49 (s, 2H), 7.00(dd, J=6.8, 8.8 Hz, 1H), 7.22 (dd, J=1.2, 8.8 Hz, 1H)

Example 301

[1278]N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)-N-tetrahydro-2H-4-pyranylmethylamine

[1279] (Yellow Oil)

[1280]¹H NMR (400 MHz, CDCl₃) δ 1.20-1.32 (m, 2H), 1.50-1.62 (m, 1H),1.74-1.82 (m, 2H), 2.44 (s, 3H), 2.99 (d, J=7.2 Hz, 2H), 3.18 (d, J=4.4Hz, 2H), 3.24-3.32 (m, 2H), 3.72 (s, 6H), 3.80-3.86 (m, 2H), 3.87 (s,3H), 3.90-3.98 (m, 4H), 4.89 (t, J=4.4 Hz, 1H), 6.49 (dd, J=1.6, 6.8 Hz,1H), 6.50 (s, 2H), 7.03 (dd, J=6.8, 8.8 Hz, 1H), 7.30 (dd, J=1.6, 8.8Hz, 1H)

Example 302

[1281]N-Butyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[1282] (White Crystals)

[1283]¹H NMR (400 MHz, CDCl₃) δ 0.79-0.87 (m, 3H), 1.23-1.36 (m, 4H),1.45-1.54 (m, 2H), 1.77-1.86 (m, 2H), 2.44 (s, 3H), 3.01-3.13 (m, 3H),3.32-3.41 (m, 2H), 3.72 (s, 6H), 3.86 (s, 3H), 3.90-3.98 (m, 2H), 6.49(dd, J=1.3, 6.8 Hz, 1H), 6.50 (s, 2H), 7.02 (dd, J=6.8, 8.8 Hz, 1H),7.25 (dd, J=1.3, 8.8 Hz, 1H)

Example 303

[1284]N-Cyclobutylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

[1285] (White Amorphous)

[1286]¹H NMR (400 MHz, CDCl₃) δ 1.43-1.85 (m, 6H), 2.19-2.29 (m, 1H),2.44 (s, 3H), 3.00-3.10 (m, 3H), 3.31-3.40 (m, 2H), 3.71 (s, 6H), 3.85(s, 3H), 3.90-3.98 (m, 2H), 6.48 (dd, J=1.3, 6.8 Hz, 1H), 6.50 (s, 2H),7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.24 (dd, J=1.3, 8.8 Hz, 1H)

Example 304

[1287]N-(7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethyl-N-tetrahydro-2H-4-pyranylamine

[1288] (Light Yellow Amorphous)

[1289]¹H NMR (400 MHz, CDCl₃) δ 1.41-1.65 (m, 3H), 1.74-1.91 (m, 3H),2.08-2.17 (m, 1H), 2.93-3.08 (m, 2H), 3.11-3.18 (m, 1H), 3.30-3.40 (m,2H), 3.54-3.72 (m, 3H), 3.75-3.83 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H),3.90-3.97 (m, 2H), 6.50 (dd, J=1.3, 6.8 Hz, 1H), 6.91 (dd, J=2.4, 8.4Hz, 1H), 7.04 (dd, J=6.8, 8.8 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.25 (dd,J=1.3, 8.8 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H).

Example 305

[1290]N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranyl-N-tetrahydro-2H-4-pyranylmethylamine

[1291] (Light Yellow Amorphous)

[1292]¹H NMR (400 MHz, CDCl₃) δ 1.17-1.30 (m, 2H), 1.36-1.54 (m, 3H),1.65-1.74 (m, 2H), 1.75-1.83 (m, 2H), 2.91-3.05 (m, 3H), 3.20-3.29 (m,2H), 3.30-3.39 (m, 2H), 3.88 (s, 3H), 3.88 (s, 3H), 3.85-3.97 (m, 4H),6.50 (dd, J=1.3, 6.8 Hz, 1H), 6.91 (dd, J=2.4, 8.4 Hz, 1H), 7.02 (dd,J=6.8, 8.8 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.25 (dd, J=1.3, 8.8 Hz,1H), 7.45 (d, J=8.4 Hz, 1H).

Example 306

[1293]N-Butyl-N-[2-methoxy-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1294] (Yellow Oil)

[1295]¹H NMR (400 MHz, CDCl₃) δ 0.85 (t, J=6.8 Hz, 3H), 1.19-1.36 (m,6H), 1.49-1.55 (m, 1H), 1.70-1.77 (m, 2H), 2.87 (d, J=7.2 Hz, 2H), 2.93(t, J=7.2 Hz, 2H), 3.25-3.32 (m, 2H), 3.71 (s, 6H), 3.86 (s, 3H), 3.89(s, 3H), 3.89-3.94 (m, 2H), 6.24 (s, 2H), 6.48 (dd, J=1.6, 6.8 Hz, 1H),7.00 (dd, J=6.8, 8.8 Hz, 1H), 7.23 (dd, J=1.6, 8.8 Hz, 1H).

Example 307

[1296]N-Cyclobutylmethyl-N-[2-methoxy-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1297] (Yellow Oil)

[1298]¹H NMR (400 MHz, CDCl₃) δ 1.20-1.30 (m, 2H), 1.49-1.60 (m, 3H),1.70-1.86 (m, 6H), 2.28-2.35 (m, 1H), 2.83 (d, J=7.2 Hz, 2H), 2.95 (d,J=7.2 Hz, 2H), 3.25-3.32 (m, 2H), 3.70 (s, 6H), 3.86 (s, 3H), 3.88 (s,3H), 3.88-3.94 (m, 2H), 6.23 (s, 2H), 6.47 (dd, J=1.6, 6.8 Hz, 1H), 7.00(dd, J=6.8, 8.8 Hz, 1H), 7.21 (dd, J=1.6, 8.8 Hz, 1H)

Example 308

[1299]N-Cyclopropylmethyl-N-[2-methoxy-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1300] (Yellow Oil)

[1301]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.02 (m, 2H), 0.28-0.34 (m, 2H),0.80-0.90 (m, 1H), 1.18-1.32 (m, 2H), 1.50-1.60 (m, 1H), 1.72-1.77 (m,2H), 2.80 (d, J=6.4 Hz, 2H), 2.94 (d, J=7.2 Hz, 2H), 3.25-3.32 (m, 2H),3.71 (s, 6H), 3.86 (s, 3H), 3.88 (s, 3H), 3.88-3.94 (m, 2H), 6.24 (s,2H), 6.47 (dd, J=1.6, 6.8 Hz, 1H), 6.99 (dd, J=6.8, 8.8 Hz, 1H), 7.28(dd, J=1.6, 8.8 Hz, 1H)

Example 309

[1302]N3-Cyclopropylmethyl-N-3-tetrahydro-2H-4-pyranylmethyl-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-methoxypyrazolo[1,5-a]pyridin-3-amine

[1303] (Yellow Oil)

[1304]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.30-0.38 (m, 2H),0.82-0.96 (m, 1H), 1.28-1.43 (m, 2H), 1.57-1.72 (m, 1H), 1.79-1.89 (m,2H), 2.05 (s, 3H), 2.24 (s, 3H), 2.87 (d, J=6.6 Hz, 2H), 3.03 (d, J=7.1Hz, 2H), 3.21 (s, 6H), 3.38 (dt, J=2.0, 12.0 Hz, 2H), 3.93 (s, 3H),3.96-4.05 (m, 2H), 6.38 (s, 1H), 6.42 (dd, J=1.5, 6.8 Hz, 1H), 7.07 (dd,J=6.8, 8.8 Hz, 1H), 7.38 (dd, J=1.4, 8.8 Hz, 1H).

Example 310

[1305]N3-Cyclopropylmethyl-N-3-tetrahydro-2H-4-pyranylmethyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-methoxypyrazolo[1,5-a]pyridin-3-amine

[1306] (Yellow Oil)

[1307]¹H NMR (400 MHz, CDCl₃) δ −0.03-0.08 (m, 2H), 0.29-0.38 (m, 2H),0.78-0.94 (m, 1H), 1.24-1.38 (m, 2H), 1.50-1.66 (m, 1H), 1.73-1.84 (m,2H), 2.15 (s, 3H), 2.84 (d, J=6.8 Hz, 2H), 2.98 (d, J=7.1 Hz, 2H), 3.19(s, 6H), 3.33 (dt, J=1.6, 12.0 Hz, 2H), 3.93 (s, 3H), 3.90-4.00 (m, 2H),6.45 (dd, J=0.6, 6.8 Hz, 1H), 6.49 (s, 1H), 7.05 (dd, J=6.8, 7.3 Hz,1H), 7.36 (dd, J=0.7, 8.8 Hz, 1H), 8.19 (s, 1H).

Example 311

[1308]N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N,N-ditetrahydro-2H-4-pyranylmethylamine

[1309] (Yellow Oil)

[1310]¹H NMR (400 MHz, CDCl₃) δ 1.18-1.31 (m, 4H), 1.46-1.58 (m, 2H),1.70-1.80 (m, 4H), 2.81-2.88 (m, 4H), 3.24-3.34 (m, 4H), 3.88 (s, 3H),3.89 (s, 3H), 3.89-3.96 (m, 4H), 6.50 (dd, J=1.3, 6.8 Hz, 1H), 6.91 (dd,J=2.4, 8.4 Hz, 1H), 7.02 (dd, J=6.8, 8.8 Hz, 1H), 7.06 (d, J=2.4 Hz,1H), 7.25 (dd, J=1.3, 8.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H).

Example 312

[1311]N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1312] (Yellow Oil)

[1313]¹H NMR (400 MHz, CDCl₃) δ −0.05-0.00 (m, 2H), 0.23-0.34 (m, 2H),0.76-0.86 (m, 1H), 1.22-1.33 (m, 2H), 1.50-1.60 (m, 1H), 1.68-1.80 (m,2H), 2.02 (s, 3H), 2.74-2.86(m, 2H), 2.89-3.00 (m, 2H), 3.29 (dt, J=2.0,11.6 Hz, 2H), 3.69 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 3.88-3.94 (m,2H), 6.39 (dd, J=1.2, 6.8 Hz, 1H), 6.42 (d, J=2.0 Hz, 1H), 6.46 (d,J=2.0 Hz, 1H), 7.00 (dd, J=6.8, 9.2 Hz, 1H), 7.29 (dd, J=1.2, 9.2 Hz,1H).

[1314] The compounds of Examples 313 to 314 were synthesized accordingto the production method of Example 40.

Example 313

[1315]N-Cyclopropylmethyl-N-[2-ethyl-7-(4-ethyl-2,6-dimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

[1316] (Yellow Oil)

[1317]¹H NMR (400 MHz, CDCl₃) δ −0.04-0.02 (m, 2H), 0.32-0.40 (m, 2H),0.78-0.88 (m, 1H), 1.12-1.36 (m, 6H), 1.56-1.64 (m, 1H), 1.82-1.92 (m,1H), 2.18-2.30 (m, 1H), 2.66-2.78 (m, 4H), 2.84-2.92 (m, 2H), 3.02-3.10(m, 1H), 3.18-3.24 (m, 1H), 3.76-3.82 (m, 4H), 3.69 (s, 6H), 6.51 (s,2H), 6.57 (dd, J=1.2, 6.8 Hz, 1H), 6.99 (dd, J=6.8, 8.8 Hz, 1H), 7.40(dd, J=1.2, 8.8 Hz, 1H)

Example 314

[1318]N-Cyclopropylmethyl-N-[2-ethyl-7-(4-ethyl-2,6-dimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

[1319] (Yellow Oil)

[1320]¹H NMR (400 MHz, CDCl₃) δ −0.02-0.04 (m, 2H), 0.34-0.40 (m, 2H),0.80-0.88 (m, 1H), 1.22-1.36 (m, 2H), 1.24 (t, J=7.6 Hz, 3H), 1.35 (t,J=7.6 Hz, 3H), 1.54-1.66 (m, 1H), 1.74-1.82 (m, 2H), 2.74 (q, J=7.6 Hz,2H), 2.79 (q, J=7.6 Hz, 2H), 2.90 (d, J=6.8 Hz, 2H), 3.60 (d, J=7.2 Hz,2H), 3.30-3.38 (m, 2H), 3.73 (s, 6H), 3.92-3.98 (m, 2H), 6.55 (s, 2H),6.61 (dd, J=1.6, 6.8 Hz, 1H), 7.01 (dd, J=6.8, 8.8 Hz, 1H), 7.44 (dd,J=1.2, 8.8 Hz, 1H).

[1321] In the Examples and Production Examples throughout the presentspecification, aldehyde compounds, halogenated compounds and sulfonatessuch as dihydro-2H-pyran-3(4H)one [CAS NO.23462-75-1],(R)-3-tetrahydropyrancarboxyaldehyde [CAS NO.143810-10-0],(S)-3-tetrahydropyrancarboxyaldehyde [CAS NO.141822-85-7],(O)-3-tetrahydropyrancarboxyaldehyde [CAS NO.77342-93-9],3-formyl-5,6-dihydro-2H-pyran [CAS NO.13417-49-7],2-oxazolecarboxyaldehyde [CAS NO.65373-52-6],6-dimethylamino-2-pyridinecarboxyaldehyde [CAS NO.208110-83-2],6-dimethylamino-3-pyridinecarboxyaldehyde [CAS NO.149805-92-5],3-methyl-5-isoxazolemethanol methanesulfonate [CAS NO.96603-41-7],3-(phenylmethoxy)-1-butanol 4-methylbenzenesulfonate [CASNO.96556-29-5], [(2-bromo-1-methylethoxy)methyl]-benzene [CASNO.135364-12-4], 5-(bromomethyl)isoxazole [CAS NO.69735-35-9] and thelike may be used as starting materials.

Test Examples

[1322] Compounds of the present invention were evaluated in regard toCorticotropin-Releasing Factor Receptor (CRFR) binding affinity andinhibiton of cAMP production. The test methods and results were asfollows.

Test Example 1

[1323] <CRFR Binding Experiment>

[1324] (1) Preparation of CRFR-Expressing Cells

[1325] Membrane fraction of the cell highly expressing human CRFR₁ wasused as the experimental material for a CRFR binding experiment. TheCRFR expressing cells were prepared in the following manner. Thefull-length CRFR₁ gene was obtained from a human brain cDNA library(QuickClone™, Clontech) by PCR. The obtained DNA fragments were insertedinto cloning vectors and the base sequences were determined. cDNA havingthe correct base sequence was then relinked to an expression vector(pcDNA3.1™, Invitrogen). The CRFR1 expression vector was introduced intoHEK293 cells, and the resistant cells which grew in cell mediumcontaining G418 (1 mg/ml) were cloned by limiting dilution. From thesecloned cells, the clones with high binding affinity between the membranefraction and sauvagine per unit of protein in the binding experimentdescribed below were selected out and used for the final experiment.

[1326] (2) Preparation of Membrane Fraction

[1327] The cloned cells obtained in (1) were collected and disruptedwith an ultrasonic generator in sonicate buffer (D-PBS(−) 10 mM MgCl₂, 2mM EGTA). The suspension obtained from ultrasonic disruption wascentrifuged (46,000×g, 10 minutes), and the precipitate was resuspendedin sonicate buffer and the same procedure was repeated. The finalprecipitate was then suspended in binding buffer (D-PBS(−) 10 mM MgCl₂,2 mM EGTA, 1.5% BSA, 0.15 mM bacitracin, 1× protease inhibitor cocktail(COMPLETE™, Boehringer)), and used as the membrane fraction afteradjusting the protein concentration to 1.6 mg/ml.

[1328] (3) Binding Experiment

[1329] The sauvagine binding experiment was conducted following theprotocol of SPA™ (Amersham Pharmacia), using a 96-well plate. Theexperiment was conducted according to the SPA beads instruction manual.After allowing 40 mg of the membrane fraction protein, 0.5 mg of SPAbeads and 50 pM of ¹²⁵I-sauvagine (Amersham Pharmacia) to stand at roomtemperature for 2 hours in the presence of the test compound, themixture was centrifuged (1000×g, 5 minutes) and the radioactivity ofeach well was measured with a TopCount™ (Packard).

[1330] (4) Calculation of Binding Affinity

[1331] The radioactivity for non-radioactive sauvagine added in a1000-fold excess was subtracted from each value as the non-specificbinding, and the radioactivity of a sample without addition of the testsubstance (control) was defined as 100%, with each value represented asa percentage (% of control). A graph was drawn with the concentration ofthe test substance plotted on the horizontal axis and the percentage (%of control) plotted on the vertical axis, and the concentration whichresulted in a 50% value for the percentage (% of control) was determinedfrom the graph to calculate the IC₅₀ value.

Test Example 2

[1332] <cAMP Production Inhibition Experiment Using AtT-20 Cells>

[1333] (1) Test Procedure

[1334] The AtT-20 cells were of a mouse pituitary gland tumor-derivedcell line which is known to respond to Corticotropin-Releasing Factor(CRF), leading to activation of the intracellular adenylate cyclasesystem, production of cyclic AMP (cAMP), and release ofadenocorticotropic hormone (ACTH) (Biochem. Biophys. Res. Com. 106,1364-1371, 1982). For the experiment, the cells (1×10⁵) were suspendedin D-MEM medium (0.1% FBS) and seeded in a 96-well plate,phosphodiesterase inhibitor (IBMX, Calbiochem) was added to a finalconcentration of 1 mM, and were cultured at 37° C. for 30 minutes. Adilution of the test compound was added, culturing was continued for 30minutes at 37° C., and CRF (30 nM) was added and culturing was continuedfor 30 minutes at 37° C. The cells were collected by centrifugation(500×g, 5 minutes) and lysed with lysis buffer (0.2%dodecyltrimethylammonium bromide), and the intracellular cAMP productionwas quantified by the HTRF method. A cAMP kit HTRF (CIS Diagnostics Co.,Ltd.) was used for the cAMP quantification.

[1335] (2) Calculation of cAMP Production Inhibition

[1336] The obtained data were processed in the following manner. ThecAMP production of cells to which 30 nM CRF had been added was definedas 100% (control), and the value for each specimen was represented as apercentage (% of control). A graph was drawn with the concentration ofthe test substance plotted on the horizontal axis and the percentage (%of control) plotted on the vertical axis, and the concentration whichresulted in a 50% value for the percentage (% of control) was determinedfrom the graph to calculate the IC₅₀ value.

[1337] <Test Results>

[1338] In Test Example 1, the compound of the invention exhibitedexcellent binding affinity for CRFR, with an IC₅₀ value of 5-5000 nM. InTest Example 2, the compound of the invention exhibited excellentinhibition against CRF-dependent cAMP production. Some of the resultsare shown below in Table 1. TABLE 1 CRF1 receptor Adenylate cyclaseCompound No. binding affinity activity (Example No.) IC₅₀ (nM) IC₅₀ (nM)Example 3 50 130 Example 6 160 200 Example 25 210 550 Example 27 55 300Example 103 90 400 Example 108 50 20

INDUSTRIAL APPLICABILITY

[1339] As explained above, the present invention provides novelpyrazolo[1,5-a]pyridine compounds having CRF receptor antagonisticactivity, their salts and novel pharmaceutical compositions comprisingthem. The compounds of the invention or their salts exhibit excellentantagonism against CRF receptors and particularly against CRF1 receptor,while having low toxicity and high safety, and are therefore highlyuseful as drugs. The compounds of the invention and pharmaceuticalcompositions comprising them are useful for treatment or prevention ofdiseases associated with CRF and/or CRF receptors, and particularly theyare useful as therapeutic or prophylactic agents for depression anddepressive symptoms (major depression, single-episode depression,recurrent depression, depression-induced child abuse, postpartumdepression, etc.), mania, anxiety, generalized anxiety disorder, panicdisorder, phobias, obsessive-compulsive disorder, posttraumatic stressdisorder, Tourette's syndrome, autism, affective disorder, dysthymia,bipolar disorder, cyclothymic personality, schizophrenia, peptic ulcer,irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea,constipation, postoperative ileus, stress-associated gastrointestinaldisorders, nervous vomiting, and the like.

1. A compound represented by the general formula:

[wherein R¹ represents hydrogen, halogen, nitro, cyano or the formula-G¹-R^(1a) (wherein G¹ represents a single bond, methylene, oxygen,sulfur, sulfinyl, sulfonyl, —C(O)—, —C(O)O—, —OC(O)—, —NR^(1b)—,—C(O)—NR^(1b)—, —S(O)₂—NR^(1b)—, —NR^(1b)—C(O)— or —NR^(1b)—S(O)₂—; andR^(1a) and R^(1b) each independently represent hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl or C₅₋₈ cycloalkenyl); R²,R³ and R⁴ each independently represent hydrogen, halogen, cyano, nitro,hydroxyl, C₆₋₁₄ aryl, a 5- to 14-membered heteroaryl group or theformula -G²-R^(2a) (wherein G² represents a single bond, C₁₋₆ alkylene,oxygen, sulfur, sulfinyl, sulfonyl, —C(O)—, —C(O)O—, —OC(O)—, NR^(2b),—C(O)—NR^(2b)—, —S(O)₂—NR^(2b)—, NR^(2b)—C(O) or —NR^(2b)—S(O)₂—; R^(2a)and R^(2b) each independently represent hydrogen, C₁₋₆ alkyl optionallysubstituted with 1-3 halogen, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈cycloalkyl or C₅₋₈ cycloalkenyl); R² and R³ or R³ and R⁴ may bondtogether to form a 5- to 7-membered ring optionally containing 1 to 4hetero atoms in the ring and optionally containing carbonyl in the ring;R⁵ and R⁶ each independently represent the formula —X⁵—X⁶-X⁷ (wherein X⁵represents a single bond or —CO—; X⁶ represents a single bond,—NR^(3a)—, oxygen, sulfur, sulfinyl, sulfonyl, C₁₋₁₀ alkylene, C₂₋₁₀alkenylene or C₂₋₁₀ alkynylene; and X⁷ and R^(3a) each independentlyrepresent hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈cycloalkyl, C₅₋₈ cycloalkenyl, C₆₋₁₄ aryl, a 5- to 14-memberedheteroaryl group, a 4- to 14-membered heterocyclic group, a 9- to11-membered benzene fused ring group, an 8- to 11-membered heteroarylfused ring group or a bicyclic 7- to 12-membered hydrocarbon ringgroup); R⁵ and R⁶ may bond together to form a 5- to 10-membered ringoptionally containing 1 to 4 hetero atoms in the ring and optionallycontaining carbonyl in the ring; R⁶ and R² may bond together to form a6- to 7-membered ring optionally containing 1 or 2 hetero atoms in thering and optionally containing carbonyl in the ring; and Ar representsC₆₋₁₄ aryl, a 5- to 14-membered heteroaryl group, a 9- to 11-memberedbenzene fused ring group or an 8- to 11-membered heteroaryl fused ringgroup; with the proviso that R^(1a), R^(1b), R^(3a), X⁶, X⁷ and Ar mayeach independently have 1 to 4 groups selected from Substituent Group Abelow; <Substituent Group A> The group consisting of methylenedioxy,ethylenedioxy and the formula -V¹-V²-V³ (wherein V¹ represents a singlebond, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene, oxygen, sulfur,carbonyl, —CO—O—, —O—CO— or —NR^(3b)—; V² represents a single bond orC₁₋₆ alkylene; and V³ and R^(3b) each independently represent C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl,C₆₋₁₄ aryl, a 5- to 14-membered heteroaryl group, a 4- to 14-memberedheterocyclic group, hydrogen, halogen, hydroxyl, cyano, C₁₋₆ alkoxy orthe formula —N(R^(3c))R^(3d) (wherein R^(3c) and R^(3d) eachindependently represent hydrogen or C₁₋₆ alkyl))], a salt thereof or ahydrate of the foregoing.
 2. A compound according to claim 1, a salt ofthe compound or a hydrate of the foregoing, wherein R¹ is the formula-G¹⁰-R¹⁰ (wherein G¹⁰ represents a single bond, methylene, oxygen,sulfur, sulfinyl or sulfonyl and R¹⁰ represents C₁₋₆ alkyl optionallysubstituted with 1 to 3 halogen, C₂₋₆ alkenyl, C₂₋₆ alkynyl or C₃₋₈cycloalkyl).
 3. A compound according to claim 2, a salt of the compoundor a hydrate of the foregoing, wherein R¹⁰ is methyl, ethyl, n-propyl,iso-propyl, trifluoromethyl, difluoromethyl, monofluoromethyl,cyclopropyl or cyclobutyl.
 4. A compound according to claim 1, a salt ofthe compound or a hydrate of the foregoing, wherein R¹ is methoxy.
 5. Acompound according to claim 1, a salt of the compound or a hydrate ofthe foregoing, wherein R¹ is ethyl.
 6. A compound according to claim 1,a salt of the compound or a hydrate of the foregoing, wherein R¹ ismethylthio.
 7. A compound according to any one of claims 1 to 6, a saltof the compound or a hydrate of the foregoing, wherein R², R³ and R⁴each independently represent hydrogen, halogen, cyano, nitro, hydroxyl,or the formula -G²⁰-R²⁰ (wherein G²⁰ represents a single bond, oxygen,sulfur, sulfinyl or sulfonyl, and R²⁰ represents C₁₋₆ alkyl optionallysubstituted with 1 to 3 halogen, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl or C₃₋₈cycloalkyl).
 8. A compound according to any one of claims 1 to 6, a saltof the compound or a hydrate of the foregoing, wherein R², R³ and R⁴ arehydrogen.
 9. A compound according to any one of claims 1 to 8, a salt ofthe compound or a hydrate of the foregoing, wherein Ar is phenyl,1,3-benzodioxolyl, naphthyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl,thienyl, furanyl, imidazolyl, thiazolyl, quinolinyl, isoquinolinyl,indolinyl, benzofuranyl, benzothienyl, oxazolyl or isoxazolyl, and Armay have 1 to 4 groups selected from Substituent Group B below;<Substituent Group B> The group consisting of halogen, cyano, hydroxyl,nitro, methylenedioxy, ethylenedioxy, the formula -V⁴-V⁵ (wherein V⁴represents a single bond, oxygen, sulfur, sulfinyl or sulfonyl and V⁵represents C₁₋₆ alkyl optionally substituted with 1 to 3 halogen or C₃₋₈cycloalkyl) and the formula —N(R^(5a))R^(5b) (wherein R^(5a) and R^(5b)each independently represent hydrogen or C₁₋₆ alkyl).
 10. A compoundaccording to any one of claims 1 to 9, a salt of the compound or ahydrate of the foregoing, wherein Ar is phenyl or pyridyl, and Ar mayoptionally have 1 to 3 groups selected from Substituent Group B in claim9.
 11. A compound according to claim 9 or 10, a salt of the compound ora hydrate of the foregoing, wherein Substituent Group B is the groupconsisting of halogen, cyano, C₁₋₆ alkyl optionally substituted with 1to 3 halogen, C₃₋₈ cycloalkyl, dimethylamino and C₁₋₆ alkoxy optionallysubstituted with 1 to 3 halogen.
 12. A compound according to any one ofclaims 1 to 8, a salt of the compound or a hydrate of the foregoing,wherein Ar is the formula:

(wherein R⁴⁰ and R⁴¹ each independently represent methoxy, ethoxy,ethyl, methyl, dimethylamino or halogen, R⁴² represents hydrogen,methoxy, methyl, dimethylamino or halogen, and Z¹ and Z² eachindependently represent methine or nitrogen).
 13. A compound accordingto claim 12, a salt of the compound or a hydrate of the foregoing,wherein Z¹ and Z² are methine.
 14. A compound according to any one ofclaims 1 to 13, a salt of the compound or a hydrate of the foregoing,wherein X⁵ is a single bond, and X⁶ is a single bond, C₁₋₆ alkyleneoptionally having 1 to 3 groups selected from Substituent Group A, C₂₋₆alkenylene optionally having 1 to 3 groups selected from SubstituentGroup A or C₂₋₆ alkynylene optionally having 1 to 3 groups selected fromSubstituent Group A.
 15. A compound according to any one of claims 1 to13, a salt of the compound or a hydrate of the foregoing, wherein X⁵ isa single bond, and X⁶ is a single bond or C₁₋₆ alkylene optionallyhaving 1 to 3 groups selected from Substituent Group C below;<Substituent Group C> The group consisting of halogen, hydroxyl, C₁₋₆alkoxy, nitrile, C₃₋₈ cycloalkyl, and C₁₋₆ alkyl.
 16. A compoundaccording to any one of claims 1 to 13, a salt of the compound or ahydrate of the foregoing, wherein X⁵ is a single bond, and X⁶ is asingle bond, 12-ethylene or methylene.
 17. A compound according to anyone of claims 1 to 16, a salt of the compound or a hydrate of theforegoing, wherein X⁷ is C₁₋₁₀ alkyl optionally having 1 to 3 groupsselected from Substituent Group A, C₂₋₁₀ alkenyl optionally having 1 to3 groups selected from Substituent Group A, C₂₋₁₀ alkynyl optionallyhaving 1 to 3 groups selected from Substituent Group A, C₃₋₈ cycloalkyloptionally having 1 to 3 groups selected from Substituent Group A, C₅₋₈cycloalkenyl optionally having 1 to 3 groups selected from SubstituentGroup A, C₆₋₁₄ aryl optionally having 1 to 3 groups selected fromSubstituent Group A, a 5- to 14-membered heteroaryl group optionallyhaving 1 to 3 groups selected from Substituent Group A, a 4- to14-membered heterocyclic group optionally having 1 to 3 groups selectedfrom Substituent Group A or a bicyclic 7- to 12-membered hydrocarbonring group optionally having 1 to 3 groups selected from SubstituentGroup A.
 18. A compound according to any one of claims 1 to 16, a saltof the compound or a hydrate of the foregoing, wherein X⁷ is C₁₋₁₀ alkyloptionally having 1 to 3 groups selected from Substituent Group A, C₃₋₈cycloalkyl optionally having 1 to 3 groups selected from SubstituentGroup A, a 5- to 6-membered heteroaryl group optionally having 1 to 3groups selected from Substituent Group A or a 4- to 7-memberedheterocyclic group optionally having 1 to 3 groups selected fromSubstituent Group A.
 19. A compound according to any one of claims 1 to16, a salt of the compound or a hydrate of the foregoing, wherein X⁷ isC₁₋₁₀ alkyl optionally having 1 to 3 groups selected from SubstituentGroup D below, C₃₋₈ cycloalkyl optionally having 1 to 3 groups selectedfrom Substituent Group D below, a 5- to 6-membered heteroaryl groupoptionally having 1 to 3 groups selected from Substituent Group D belowor a 4- to 7-membered heterocyclic group optionally having 1 to 3 groupsselected from Substituent Group D below; <Substituent Group D> The groupconsisting of halogen, hydroxyl, C₁₋₆ alkoxy, nitrile, C₃₋₈ cycloalkyl,dimethylamino and C₁₋₆ alkyl.
 20. A compound according to any one ofclaims 1 to 16, a salt of the compound or a hydrate of the foregoing,wherein X⁷ is hydrogen, C₁₋₁₀ alkyl optionally having 1 or 2 groupsselected from Substituent Group E below, C₃₋₈ cycloalkyl optionallyhaving 1 or 2 groups selected from Substituent Group E below,tetrahydrofuranyl optionally having 1 or 2 groups selected fromSubstituent Group E below, tetrahydrothiophenyl optionally having 1 or 2groups selected from Substituent Group E below, dihydropyranyloptionally having 1 or 2 groups selected from Substituent Group E below,tetrahydropyranyl optionally having 1 or 2 groups selected fromSubstituent Group E below, dioxolanyl optionally having 1 or 2 groupsselected from Substituent Group E below, pyrrolidin-2-onyl optionallyhaving 1 or 2 groups selected from Substituent Group E below,dihydrofuran-2-onyl optionally having 1 or 2 groups selected fromSubstituent Group E below, furanyl optionally having 1 or 2 groupsselected from Substituent Group E below, thienyl optionally having 1 or2 groups selected from Substituent Group E below, pyrrolidinyloptionally having 1 or 2 groups selected from Substituent Group E below,piperidyl optionally having 1 or 2 groups selected from SubstituentGroup E below, oxazolyl optionally having 1 or 2 groups selected fromSubstituent Group E below, isoxazolyl optionally having 1 or 2 groupsselected from Substituent Group E below, thiazolyl optionally having 1or 2 groups selected from Substituent Group E below, pyrrolyl optionallyhaving 1 or 2 groups selected from Substituent Group E below, pyrazolyloptionally having 1 or 2 groups selected from Substituent Group E below,morpholinyl optionally having 1 or 2 groups selected from SubstituentGroup E below, dioxanyl optionally having 1 or 2 groups selected fromSubstituent Group E below or pyridyl optionally having 1 or 2 groupsselected from Substituent Group E below; <Substituent Group E> The groupconsisting of hydroxyl, methyl, ethyl, methoxy, dimethylamino, cyano,chlorine and fluorine.
 21. A compound according to claim 20, a salt ofthe compound or a hydrate of the foregoing, wherein Substituent Group Eis the group consisting of methyl, methoxy, dimethylamino, chlorine andfluorine.
 22. A compound according to any one of claims 1 to 16, a saltof the compound or a hydrate of the foregoing, wherein X⁷ is hydrogen,C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, tetrahydrofuranyl, tetrahydrothiophenyl,dihydropyranyl, tetrahydropyranyl, dioxolanyl, pyrrolidin-2-onyl,dihydrofuran-2-onyl, furanyl, thienyl, pyrrolidinyl, piperidyl,oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, pyrazolyl, morpholinyl,dioxanyl or pyridyl.
 23. A compound according to any one of claims 1 to16, a salt of the compound or a hydrate of the foregoing, wherein X⁷ ishydrogen, C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydropyranyl, dioxolanyl, furanyl, thienyl,oxazolyl, dioxanyl, pyridyl, piperidyl or thiazolyl.
 24. A compoundrepresented by the general formula:

[wherein R^(7a) represents hydrogen, nitro, —NO or —NHR^(7d) (whereinR^(7d) represents hydrogen, t-butoxycarbonyl or benzyloxycarbonyl);R^(7c) represents methylene, oxygen or sulfur; and R^(7b) representshydrogen, halogen, the formula:

(wherein R_(8a) and R^(8b) each independently represent hydrogen or C₁₋₆alkyl, or R^(8a) and R^(8b) may bond together to form 1,2-ethylene,1,3-propylene or 2,3-dimethylbutan-2,3-diyl), the formula:

(wherein R^(8c), R^(8d) and R_(8e) each independently represent C₁₋₆alkyl) or the formula:

(wherein R⁴⁰ and R⁴¹ each independently represent methoxy, ethoxy,ethyl, dimethylamino, methyl or halogen, R⁴² represents hydrogen,methoxy, methyl or halogen, and Z¹ and Z² each independently representmethine or nitrogen), with the proviso that compounds satisfying thefollowing conditions (1), (2) or (3) are not included in the abovedefinitions: (1) R^(7c) is oxygen, R^(7b) is hydrogen and R^(7a) ishydrogen, nitro, —NO or —NH₂, (2) R^(7c) is sulfur, R^(7b) is hydrogenand R_(7a) is nitro or —NH₂, or (3) R⁷, is methylene, R^(7b) is hydrogenand R^(7a) is —NO], a salt thereof or a hydrate of the foregoing.
 25. Acompound according to claim 24, a salt of the compound or a hydrate ofthe foregoing, wherein R^(7a) and R^(7b) are hydrogen.
 26. A compoundaccording to claim 24, a salt of the compound or a hydrate of theforegoing, wherein R^(7b) is not hydrogen.
 27. A compound represented bythe general formula:

[wherein R⁵ and R⁶ have the same definitions as R⁵ and R₆ in claim 1,respectively; R_(7c) represents methylene, oxygen or sulfur; and R₇represents halogen, the formula:

(wherein R^(8a) and R^(8b) each independently represent hydrogen or C₁₋₆alkyl, or R^(8a) and R_(8b) may bond together to form 1,2-ethylene,1,3-propylene or 2,3-dimethylbutan-2,3-diyl), or the formula:

(wherein R_(8C), R^(8d) and R^(8e) each independently represent C₁₋₆alkyl)], a salt thereof or a hydrate of the foregoing.
 28. ACorticotropin-Releasing Factor (CRF) receptor antagonist comprising acompound according to claim
 1. 29. A Corticotropin-Releasing Factor(CRF)-1 receptor or Corticotropin-Releasing Factor (CRF)-2 receptorantagonist comprising a compound according to claim
 1. 30. A therapeuticor prophylactic agent for a disease associated withCorticotropin-Releasing Factor (CRF), comprising a compound according toclaim
 1. 31. A therapeutic or prophylactic agent for depression,depressive symptom, mania, anxiety, generalized anxiety disorder, panicdisorder, phobias, obsessive-compulsive disorder, posttraumatic stressdisorder, Tourette's syndrome, autism, affective disorder, dysthymia,bipolar disorder, cyclothymic personality or schizophrenia, comprising acompound according to claim
 1. 32. A therapeutic or prophylactic agentfor a depressive symptom which is major depression, single-episodedepression, recurrent depression, depression-induced child abuse orpostpartum depression, comprising a compound according to claim
 1. 33. Atherapeutic or prophylactic agent for peptic ulcer, irritable bowelsyndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation,postoperative ileus, stress-associated gastrointestinal disorders ornervous vomiting, comprising a compound according to claim
 1. 34. Atherapeutic or prophylactic agent for Alzheimer's disease, seniledementia of Alzheimer's type, neurodegenerative disease, multi-infarctdementia, senile dementia, anorexia nervosa, eating disorder, obesity,diabetes, alcohol dependence, pharmacophilia, drug withdrawal symptoms,alcohol withdrawal symptoms, sleep disorder, insomnia, migraine,stress-induced headache, muscle contraction induced headache, ischemicneuronal damage, excitotoxic neuronal damage, stroke, progressivesupranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis,muscular spasm, chronic fatigue syndrome, psychosocial dwarfism,epilepsy, head trauma, spinal cord injury, cheirospasm, spasmodictorticollis, cervicobrachial syndrome, primary glaucoma, Meniere'ssyndrome, autonomic imbalance, alopecia, neurosis, hypertension,cardiovascular disorder, tachycardia, congestive heart failure,hyperventilation syndrome, bronchial asthma, apneusis, sudden infantdeath syndrome, inflammatory disorder, pain, allergosis, impotence,menopausal disorder, fertilization disorder, infertility, cancer, HIVinfection-induced immune dysfunction, stress-induced immune dysfunction,hemorrhagic stress, Cushing's syndrome, thyroid function disorder,encephalomyelitis, acromegaly, incontinence or osteoporosis, comprisinga compound according to claim
 1. 35. The use of a compound according toclaim 1 or a salt thereof for the manufacture of a.Corticotropin-Releasing Factor (CRF) receptor antagonist.
 36. The use ofa compound according to claim 1 or a salt thereof for the manufacture ofa Corticotropin-Releasing Factor (CRF)-1 receptor antagonist orCorticotropin-Releasing Factor (CRF)-1 receptor antagonist.
 37. The useof a compound according to claim 1 or a salt thereof for the manufactureof a therapeutic or prophylactic agent for depression, depressivesymptom, mania, anxiety, generalized anxiety disorder, panic disorder,phobia, obsessive-compulsive disorder, posttraumatic stress disorder,Tourette's syndrome, autism, affective disorder, dysthymia, bipolardisorder, cyclothymic personality, schizophrenia, peptic ulcer,irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea,constipation, postoperative ileus, stress-associated gastrointestinaldisorders or nervous vomiting.
 38. A therapeutic or prophylactic methodfor a disease associated with Corticotropin-Releasing Factor (CRF)receptor, comprising single or multiple administration of atherapeutically effective dose of a compound according to claim 1 or asalt thereof to a patient with a disease associated withCorticotropin-Releasing Factor (CRF) receptor.